B Anc

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Anc GnRH-CRZ GnRH GnRH ? CRZ GnRH CRZ A GnRH

 6.4.1.Ancient origin of neuromediators and receptors in metazoan 6.4.2. Non-peptidic neuromediators as potential targets for neuroendocrine disruption: a phylogenetic approach 6.4.3. The "One Health concept"

Abstract

In human, as in the other mammals, the neuroendocrine control of reproduction is ensured by the brain-pituitary gonadotropic axis. Multiple internal and environmental cues are integrated via brain neuronal networks, ultimately leading to the modulation of the activity of gonadotropin-releasing hormone (GnRH) neurons. The decapeptide GnRH is released into the hypothalamic-hypophyseal portal blood system, and stimulates the production of pituitary glycoprotein hormones, the two gonadotropins, luteinizing hormone (LH) and folliclestimulating hormone (FSH). A novel actor, the neuropeptide kisspeptin (Kiss), acting upstream of GnRH, has attracted increasing attention in recent years. Other neuropeptides, such as gonadotropin-inhibiting hormone (GnIH) / RF-amide related peptide (RFRP), and other members of the RF-amide peptide superfamily, as well as various non-peptidic neuromediators such as dopamine and serotonin also provide a large panel of stimulatory or inhibitory regulators. This paper addresses the origin and evolution of the vertebrate gonadotropic axis. Brain-pituitary neuroendocrine axes are typical of vertebrates, the pituitary gland, mediator and amplifier of brain control on peripheral organs, being a vertebrate innovation. The paper reviews, from molecular and functional perspectives, the evolution across vertebrate radiation of some key-actors of the vertebrate neuroendocrine control of reproduction, and traces back their origin along the vertebrate lineage and in other metazoa before the emergence of vertebrates. A focus is given on how gene duplications, resulting from either local events or from whole genome duplication events (WGD), and followed by paralogous gene loss or conservation, might have shaped the evolutionary scenarios of current families of key-actors of the gonadotropic axis.

Introduction

The neuroendocrine control of reproduction has been extensively investigated in mammals (for review: (370)). Two pituitary hormones, the gonadotropins, i.e. luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are released in the general blood circulation and regulate gonad activity. The synthesis and release of gonadotropins is mainly controlled by a neuropeptide, gonadotropin-releasing hormone (GnRH), produced by hypothalamic neurosecretory neurons and released into the portal blood system connecting the median eminence to the adenohypophysis. GnRH neuron activity is itself regulated by various brain neuromediators, which allows the integration of multiple environmental and internal cues in the course of developmental or seasonal control of reproduction (Figure 1).

Other major physiological functions in mammals are similarly controlled by brain-pituitaryperipheral gland axes, such as the thyrotropic axis (brain-pituitary-thyroid) for development and metabolism, the somatotropic axis (brain-pituitary-liver) for body growth, the corticotropic axis (brain-pituitary-adrenal gland) for stress and metabolism. The pituitary gland and its role as a relay between the brain and peripheral glands or peripheral organs, is considered as an innovation of the vertebrate lineage (for review: (641,738,740)). The pituitary gland with its production of pituitary hormones under the control of brain neurohormones is a common feature to all vertebrates, even though some anatomical variations in the brain-pituitary relationships are observed. In mammals as in other tetrapods, hypophysiotropic neurons project to the median eminence and neurohormones are released into the pituitary portal system which irrigates the adenohypophysis, while, in teleost fishes, hypophysiotropic neurons directly project up to the adenohypophysis which exhibits a high Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] regionalization of pituitary cell types (231,287). In cyclostomes (hagfish and lamprey), brain neuropeptides reach the adenohypophysis by diffusion from the third ventricle, which may represent the ancestral pattern of connection between the hypothalamus and the pituitary in vertebrates (for review: (738)).

We review here current information and hypotheses on the origin, conservation and variations of the key actors of the vertebrate brain-pituitary control of reproduction, with a special attention to the impact of gene and genome duplication events in the evolutionary scenario of their molecular families.

Looking for the origin and evolution of the neuroendocrine control of reproduction

Objectives

Comparative biologists have been investigating the control of reproduction as well as of other physiological functions in non-mammalian vertebrates and other metazoa. Comparative studies not only provided specific information on species of interest, but also led to major advances for basic research. A remarkable example concerns the "neurosecretion" process, i.e. the ability of certain neurons to synthesize and release hormones, a property exhibited for instance by GnRH neurons. Hypothalamic neurosecretory neurons were first described in 1928 in a teleost fish species, Phoxinus laevis, by Ernst Scharrer (679), who established the concept of "neurosecretion", a few years after the description by Carl [START_REF] Speidel | Gland cells of internal secretion in the spinal cord of skates[END_REF] (742) of some "glandular" neurons in the spinal cord of chondrichthyan fish, the skates (for reviews:

(665, 678)). In the same line, the first RF-amide peptide, designated after the C-terminal arginine (R) and amidated phenylalanine (F) residues, has been isolated in 1977 from the ganglia of a mollusk, the Venus clam, Macrocallista limbosa (623). Since then, an increasing number of RF-amide peptides have been identified in all metazoa, constituting the RF-amide Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] superfamily and including some brain peptides involved in the neuroendocrine control of reproduction in vertebrates (see section 5).

Comparative and evolutionary reproductive neuroendocrinology is arousing interest for various disciplinary fields, thanks to the variety of biological models investigated and the availability of tools such as genome sequences. There is an increasing attention to teleosts (e.g. zebrafish) as vertebrate models for biomedical research, and an increasing diversity of species investigated worldwide for their relevance to agriculture, aquaculture, conservation, or environmental assessment. Comparative and evolutionary neuroendocrinology aims at tracing back the roots and the evolution of the neuroendocrine systems, from molecular and functional perspectives, and at inferring their roles in the evolution of metazoan species and lifecycles. For agronomic sciences, it contributes to increase basic and applied knowledge for sustainable control of reproductive cycles in captivity, for understanding domestication processes, for diversifying cultured species such as in aquaculture, and promoting sustainable agro/aqua-systems. For conservation biology, it provides new knowledge for understanding the role of neuroendocrine systems in species adaptation and adaptability to environmental factors, a crucial topic in the context of global, climatic and anthropogenic changes. In biomedical sciences, comparative and evolutionary neuroendocrinology contributes to innovative advances by providing alternative vertebrate models suitable for experimentation such as zebrafish, by revealing the evolutionary conservation of key neuroendocrine actors and of their sequences, the mutation of which may lead to severe pathologies, or by highlighting common processes in the impact of environmental stressors and pollutants leading to the disruption of the reproductive capacity of wild species, domesticated animals or humans, in the frame of the "One health" concept.

Bases of phylogeny

Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] In order to investigate and compare neuroendocrine systems in an evolutionary perspective, it is necessary to relate the data obtained in a given species to the phylogenetical position of this species. Phylogeny of vertebrates and metazoa is by itself an ongoing research topic, based on multiple disciplinary fields such as paleontology, comparative anatomy, embryology, and more recently molecular systematics and phylogenomics. We are using, in the present manuscript, recent and largely consensual advances in vertebrate and metazoa phylogeny.

2.2.1. Phylogeny of vertebrates (Figure 2)

All vertebrate species belong to a monophyletic clade, i.e. a group of species that consists of all the descendants of a common ancestor. Among the vertebrate clade, several "subclades" can be distinguished. The most ancient (or most basal) is represented by cyclostomes (such as lampreys and hagfish). Cyclostomes are the sister clade of all other vertebrates characterized by the innovation of the jaws and therefore called gnathostomes. The gnathostome clade is further divided into two sister clades, the chondrichthyans (such as sharks and ray fishes) and the osteichthyans. The osteichthyan clade is further divided into two major sister clades: (i) the actinopterygian clade that encompasses teleost fishes (the largest current group of vertebrates with more than 25,000 species including most fisheries, aquaculture and model fish species) and some other "fish" clades such as holosteans (gar); (ii) the sarcopterygian clade that encompasses the tetrapods including mammals, and also some "fish" species such as the coelacanth, representative species of actinistia, a basal group among sarcopterygians.

The current vertebrate phylogeny highlights in particular that the name "fish" is not by itself phylogenetically relevant, as it may apply to species from very distinct vertebrate clades, such as cyclostomes (lampreys), chondrichthyans (sharks), actinopterygians (gar, zebrafish), and sarcopterygians (coelacanth). Thus, human and coelacanth are phylogenetically closer than coelacanth and zebrafish or than human and zebrafish. 10 2.2.2. Phylogeny of metazoa (Figure 3) While the broad lines of vertebrate phylogeny remained similar to the traditional classification based on paleontology, comparative anatomy and embryology, the recent advances in molecular systematics and phylogenomics largely challenged the classification of other metazoa [START_REF] Adoutte | The new animal phylogeny: reliability and implications[END_REF]170). We present here a most consensual phylogeny of the major clades of metazoa. Bilateria, the major clade among metazoa, gather animals with a bilateral symmetry (at least at the embryonic stage) and with three tissue layers (endoderm, mesoderm, ectoderm) during embryogenesis so that they are also called triploblastics. Besides bilateria, the respective classification of the basal groups of metazoa, such as cnidaria (corals), porifera (sponges), and others, is still largely under debate. Bilateria encompass two major clades, on the one hand, deuterostomes which include chordates and among chordate the vertebrates, and on the other hand, protostomes which include two major sister clades, ecdysozoa (flatworms, insects, crustaceans,..) and lophotrochozoa (annelids, mollusks, ...) [START_REF] Adoutte | The new animal phylogeny: reliability and implications[END_REF]608).

Phylogeny of molecular families versus phylogeny of species

Phylogenetical analyses of protein families of interest, such as hormones / neuropeptides / receptors / enzymes, potentially involved in the neuroendocrine control of reproduction, are performed in order to compare sequences between various vertebrate or metazoa species.

Phylogenetic trees of molecular families highlight protein sequence conservation or divergence and lead to hypotheses on evolutionary relationships between sequences and possible functional variations. The phylogenetic tree of a given protein family does not always follow the phylogenetic tree of the corresponding species, which makes it possible to infer further hypotheses on the duplication, divergence, convergence and loss of corresponding protein-coding genes. Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

Origin and fate of duplicated genes

Gene duplications produce so-called paralogous genes, and are considered as major drivers of evolution, as they provide new gene pools allowing the emergence of novel functions, organs and regulatory processes.

Intra-gene duplication

Besides gene duplication, intra-gene duplication of exons also contributes to the evolution of neuroendocrine systems, as exemplified by the multiple copies of thyrotropin-releasing hormone (TRH) peptide coded by the TRH gene (397), or by up to three homologous gonadotropin-inhibiting hormone (GnIH) peptides coded by the GnIH gene (see section 5).

Intra-gene peptide duplication may lead to the amplification of peptide production or, after mutations of some of the duplicated sequences, to the production of distinct peptides with potentially differential activities.

Local gene duplication

Gene duplication produces paralogous genes and may originate from local genomic events, targeting either a specific gene or a limited genomic region. If no major genomic restructuration occurs afterwards, local duplication events can be traced back in extant species genomes by tandem position or by a relatively close position of the paralogous genes on the same chromosome. For instance, a local gene duplication in early gnathostomes is hypothesized to be at the origin of the two gonadotropin receptors, LH receptor and FSH receptor, positioned in tandem in tetrapods, including human, as well as in basal sarcopterygian (coelacanth) and basal actinopterygian (gar) (468). The conservation of the tandem position throughout vertebrate evolution may be related to conserved coordination of Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] gene expression, via chromatin accessibility and common regulatory factors. In the primate lineage, a specific gene duplication of the LH beta subunit (LHβ) gene, that occurred much more recently, is at the origin of the chorionic gonadadotropin beta subunit (CGβ), involved in the regulation of an innovative reproductive organ, the placenta; further CGβ duplications led to up to six hCGβ genes in human arranged in a gene cluster together with the LHβ gene on chromosome 19 (for review: ( 522)) (see section 3).

Whole genome duplication

Gene duplications may also originate from whole genome duplication events (WGD), as proposed by Ohno in vertebrates (548). Gene paralogs stemming from WGD are thus named "ohnologs" by certain authors. It is now consensually admitted that two successive WGD, referred to as "1R" and "2R", for "first round" and "second round" of whole genome duplications, have occurred at the base of the vertebrate lineage (Figure 2), even though the exact timing of the second WGD is still under discussion (for review: (284)). These 1R and 2R WGD, which occurred about 450 Million years ago, are still traceable in the current human genome, by fourway paralogous regions (paralogons) covering a large proportion of the human genome (145). It has been advanced that the two rounds of WGD may have contributed to the evolutionary success of the vertebrate lineage.

Genome sequencing of teleost fish models, such as medaka, fugu or zebrafish, revealed an additional WGD, referred to as 3R (for 3 rd round of WGD) (for review: (484)) (Figure 2).

When occurred this 3R WGD in the actinopterygian lineage event, remained under debate until recently, as more genomes became available including for species of key phylogenetic positions such as a non-teleost actinopterygian, an holostean, the spotted gar [START_REF] Braasch | The spotted gar genome illuminates vertebrate evolution and facilitates human-to-teleost comparisons[END_REF], or a basal teleost, an elopomorph, the eel (273,274). These studies concluded that, in the course of actinopterygian evolution, the 3R would have specifically occurred in the teleost lineage, in Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] an early teleost ancestor before the emergence of the basal group of elopomorphs. This 3R event is thus also referred to as TWGD or TGD (teleost whole genome duplication) (586), and is hypothesized to have contributed to the diversification of this group, the largest among vertebrates. 2.3.4. Definition of homologous, orthologous, paralogous, or ohnologous genes These definitions are important in order to analyze the molecular and functional relationships and diversification processes among molecular families including those involved in neuroendocrine systems. Homologous genes are present in the same or different species, and all derive from a common ancestral gene. Homologous genes include orthologous, paralogous and ohnologous genes. Orthologous genes are genes present in different species and evolved from a common ancestral gene in the course of speciation (emergence of new species over the course of evolution). Paralogous genes are present in the same or in different species and result from the duplication of a common ancestral gene, either via local gene specific duplication or via WGD. Ohnologs are paralogs resulting from WGD.

Fate of duplicated genes

Gene duplication produces two paralogs, which initially exert the same redundant function. In most cases, this redundancy leads to a rapid loss of one of the two paralogs, via accumulation of mutations due to redundancy-related lack of selective pressure. However, both paralogs may be conserved after duplication due to evolutionary selection related to amplification of initial function, or sharing of initial pleiotropic functions (subfunctionalisation), or emergence of a new function (neofunctionalisation). Duplications followed by gene amplification, subfunctionalisation, neofunctionalisation, or loss, are involved in the evolutionary scenarii of the neuroendocrine gonadotropic axis. Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019. The first experiment describing the stimulatory effects of bovine pituitary extracts on rat ovarian growth and luteinization was published in 1922 (180), demonstrating that the anterior part of the pituitary gland contains a gonadotrophic factor. It took a decade before this factor appeared to be composed of two distinct fractions in ewes, one responsible for growth of ovarian follicles and the other for luteinization (190). These two fractions were accordingly named follicle-stimulating hormone (FSH) and luteinizing hormone (LH), respectively.

Origin and evolution of gonadotropins, the pituitary relay between brain and gonads in vertebrates

Technical improvement in glycoprotein purification methods, and notably the development of ion-exchange chromatography, made possible a better assignment of the roles of LH and FSH. In hypophysectomised rats, it was found that FSH acts on granulosa cells of the Graafian follicles and LH on the theca interna and ovarian interstitial tissue, the combination of the two stimulating estrogen secretion, ovulation and corpus luteum formation (834). The dimeric nature of LH, first suggested by Li and Starman (1964), was confirmed by Papkoff and Samy (1967) (576) who characterized two dissimilar subunits in ovine LH. The biological activity of the reconstituted dimer was finally demonstrated by De la LLosa and Jutisz (1969) (382).

Another factor was also purified from the bovine pituitary gland that stimulates the thyroid (126). Homology between this thyroid-stimulating hormone (TSH) and the gonadotropins was suggested after experiments demonstrating that mammalian LH and FSH are able to stimulate Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] the thyroid of teleost fish (203,204). Soon after, it was established that LH, FSH and TSH have one interchangeable subunit, the glycoprotein hormone (GPH) α subunit, whereas the β subunit determines the hormonal specificity (609). The first amino acid sequence of an LH α subunit was deciphered in 1971 (428) and its identity with the FSH α subunit was demonstrated in 1974 (710). The first sequences of β subunits also appeared in the early 70s ((428) for LH; (417) for TSH; (710) for FSH), confirming the homology between thyrotropin and gonadotropin β subunits. It was thus established by the mid-seventies that the two pituitary gonadotropins and the thyrotropin belong to a family of dimeric glycoproteins that share the α subunit, whereas the three β subunits, which confer hormonal specificity, are derived from a common evolutionary ancestor.

The demonstration of the existence of two pituitary gonadotropins was laboriously extended to all tetrapod groups (for review: (309)); teleosts ((758), for review: (407); chondrostei (628); dipnoi (627); chondrichthyans (629)), showing that all jawed vertebrates are provided with the same pituitary gonadotropic molecules. Up to now, a single gonadotropin has been discovered in the cyclostomes, in hagfish (819) and in lamprey (741) even though, in this later species, the α subunit has still to be identified (739). Glycoprotein hormones (stricto sensu), like all other pituitary hormones, are not found before the emergence of vertebrates [START_REF] Campbell | Piecing together evolution of the vertebrate endocrine system[END_REF].

Non-pituitary gonadotropins

The presence of a luteotrophic factor in urine of pregnant women was first observed in 1927 [START_REF] Ascheim | Hypophysenvorderlappenhormon und Ovarialhormon Im Harn Von schwangeren[END_REF], leading to the development of the first pregnancy detection test. This gonadotropic factor was shown to be produced by placental cells in culture (327) and more specifically by syncytiotrophoblast cells (485) and named human chorionic gonadotropin (hCG). The similarity with LH in terms of biological activity was rapidly observed (439) and its ability to bind the same receptor as LH was later demonstrated [START_REF] Catt | Studies on a radioligand-receptor assay system for luteinizing hormone and chorionic gonadotropin[END_REF], hence the LH-CG receptor naming. Eventually, the close structural relatedness of hCG to LH was confirmed when sequencing data were made available (765). The human CGβ subunit has later been found to be expressed in the pituitary [START_REF] Birken | Isolation and characterization of human pituitary chorionic gonadotropin[END_REF] and testis [START_REF] Berger | Eutopic production of human chorionic gonadotropin beta (hCG beta) and luteinizing hormone beta (hLH beta) in the human testis[END_REF]583). Pregnant mare serum was also shown to contain a gonadotropic factor (123) that was called pregnant mare serum gonadotropin (PMSG) before its origin as a chorionic cell product was recognized and its name changed to equine chorionic gonadotropin (eCG). It was later demonstrated that, unlike their human counterparts, eCG and eLHβ subunits are encoded by the same gene (702). LHβ subunit expression also occurs in the placenta of a marsupial (482) and possibly in diverse eutherian mammals (119).

Extra-pituitary expression of LH and FSH

LH and FSH are also expressed in the gonads and the brain. The first report of gonadal expression of gonadotropin described the immunological detection of LH in human and rat Leydig cells and that of FSH in Sertoli cells (849). LHβ subunit transcripts were further characterized in elongated spermatids in the rat (910), and were found to possess an extended 5' UTR end resulting in the same coding sequence as the pituitary transcript apart from the first three amino acids of the signal peptide (909). In female rat, FSHβ, LHβ and the common α subunits are produced by theca cells, corpora lutea and oocytes, whereas granulosa cells only express LH subunits. The ovarian LHβ subunit gene uses the same alternative promoter as in the testis (680). Expression of this transcript is reduced by administration of PMSG, which activates both LH and FSH receptors in non-equine species (249,419). Interestingly, in vitro granulosa cell expression of LHβ mRNA is also decreased in response to a GnRH agonist, likely through FSH receptor activation (425). Both LH and FSH are expressed in the Siberian hamster ovary with levels varying according to the estrus cycle but in an opposite fashion as in the pituitary (699). No specific role has been described for these gonadal gonadotropins. Whether gonadal expression of gonadotropins is a common feature in mammals or other tetrapods remains to be clarified but this seems to be the case in teleosts [START_REF] Acharjee | Molecular cloning and characterization of the gonadotropin subunits GPα, FSHβ, and LHβ genes in the stinging catfish Heteropneustes fossilis: Phylogeny, seasonal expression and pituitary localization[END_REF]172,626,705,706,728,879,882). It has to be noted that the seabream ovarian LHβ subunit transcript is also extended in its 5' end, suggesting the existence of a conserved alternative and gonadal-specific promoter for the LHβ gene. However, the expression of the two ovarian gonadotropins is up-regulated by GnRH in the sea bream (879). Ovarian LHβ subunit expression in the sole also varies according to the ovarian maturation stage, like in the pituitary (706).

Another important site of expression of gonadotropins in teleosts is the brain (172,496,580,705). It was notably observed in a cichlid that the two gonadotropins expressed in the preoptic area potentially play a regulatory role on pituitary expression of gonadotropins (574). LH is also expressed in rat hypothalamus in a manner that depends on the presence of a functioning pituitary (177). Brain gonadotropins may be involved in neuronal regulation of steroid synthesis (427).

Main regulators of gonadal function

Genetic mice models where either the FSHβ (380) or LHβ (442) subunit or the FSH [START_REF] Abel | The Effect of a Null Mutation in the Follicle-Stimulating Hormone Receptor Gene on Mouse Reproduction[END_REF] or LH (908) receptor is deleted show that ovarian differentiation and growth are not dependent on pituitary gonadotropin stimulation even if FSH stimulates proliferation of granulosa cells in pre-antral follicles. In teleosts, timing of pituitary gonadotropin expression as compared to gonadal differentiation also pleads for a process that does not involve gonadotropins (518).

Mammalian FSH receptors are expressed in granulosa cells from the secondary follicle stage (follicles with at least two layers of granulosa cells) onward and LH receptor expression on theca cells rapidly follows. After puberty onset, FSH is indispensable for the cyclic recruitment of follicles (after oocytes have reached their maximal size) and terminal folliculogenesis. LH is involved in the final steps of pre-ovulatory follicle maturation, allowing meiosis to resume and inducing ovulation [START_REF] Adhikari | Molecular mechanisms underlying the activation of mammalian primordial follicles[END_REF]239,474). LH is responsible for the production of aromatizable androgens by theca cells. These androgens then reach granulosa cells where they are converted into estrogens under the stimulatory action of FSH (371,708).

At mid-cycle, granulosa cells of recruited follicles acquire LH receptor expression and initiate progesterone production, the stimulation of which is later relayed by hCG. Progesterone is essential for ovulation and for preventing further follicle maturation.

As for the ovary, pituitary gonadotropins are not required for testicular differentiation but FSH stimulates proliferation of Sertoli cells in prepubertal testis (399,448). At puberty onset, FSH promotes Sertoli cell function but its importance for spermatogenesis depends on taxonomic groups (297). LH stimulates proliferation of adult-type Leydig cells responsible for the production of steroid hormones (792) and activates steroidogenesis and therefore, spermatogenesis.

A role for gonadotropin subunit monomers or homodimers?

The gonadotropin receptors are poorly activated by gonadotropin subunit monomers or homodimers. However, the hCGβ subunit is produced in large excess in most epithelial cancers and is believed to play an autocrine angiogenic and anti-apoptotic role, possibly through interacting with components of cysteine-knot growth factor (and notably TGFβ) receptor complexes (124,303). Free glycoprotein hormone α subunit is also produced in excess by the pituitary and secreted throughout the menstrual cycle (255) and by the placenta (635). In the placenta, the free α subunit is much more potent than the intact hCG in acting synergistically with progesterone to induce decidualization of endometrial stromal cells (512) and stimulates prolactin release from human decidual cells [START_REF] Blithe | Free alpha molecules from pregnancy stimulate secretion of prolactin from human decidual cells: a novel function for free alpha in pregnancy[END_REF]. Interestingly, the free α subunit stimulates differentiation and proliferation of prolactin-producing cells in the foetal and postnatal mammalian pituitary gland [START_REF] Van Bael | Evidence for a trophic action of the glycoprotein hormone αsubunit in rat pituitary[END_REF][START_REF] Bégeot | Induction of pituitary lactotrope differentiation by luteinizing hormone β subunit[END_REF][START_REF] Chabot | Two free isoforms of ovine glycoprotein hormone alpha-subunit strongly differ in their ability to stimulate prolactin release from foetal pituitaries[END_REF] and prolactin release by frog pituitary cells in culture (544). The action of the free α subunit is not mimicked by LH or hCG heterodimer, demonstrating that the free α subunit, like hCGβ, may have a specific role independent on the activation of the gonadotropin receptors.

Structural characteristics of gonadotropins

The glycoprotein hormones are non-covalently linked heterodimers composed of an α subunit that is common to all gonadotropins and TSH and a specific β subunit that confers biological specificity. In all species, the pituitary gonadotropin subunits are transcribed from single genes although some teleost fishes may be provided with two α subunit genes, resulting from genome duplication in recent ancestors (407). The α subunit gene contains four exons, the first of which encoding the 5' untranslated region, the three others coding for a 92-100 amino acid-long protein excluding the signal peptide. All pituitary glycoprotein hormone β subunit genes contain three exons, the first one coding for the 5' untranslated region and, in some species, part of the LHβ signal peptide. The second intron-splicing site is located at the same position in all β subunit genes.

Global folding and general characteristics

The most obvious characteristics shared by the α and all β subunits are the presence of one or two glycosylation sites at conserved position and a conserved arrangement of cysteine residues. The crystal structure of hCG was resolved almost simultaneously by two different laboratories (390,883). The structure of FSH was later deciphered (206) demonstrating that the overall folding pattern of the two glycoprotein hormone dimers is very similar. Taking into account the high degree of conservation of the glycoprotein hormone subunits in vertebrates and in particular the special cysteine arrangements (with the exception of teleost FSHβ subunit as related below), it is tempting to assume that this organization is conserved among vertebrate gonadotropins. Both the α and β subunits belong to the large cysteine-knot family of proteins and more specifically to the TGF-β subfamily [START_REF] Alvarez | Comparative structure analyses of cystine knot-containing molecules with eight aminoacyl ring including glycoprotein hormones (GPH) alpha and beta subunits and GPH-related A2 (GPA2) and B5 (GPB5) molecules[END_REF][START_REF] Avsian-Kretchmer | Comparative Genomic Analysis of the Eight-Membered Ring Cystine Knot-Containing Bone Morphogenetic Protein Antagonists[END_REF]271). They present a similar folding producing flat elongated structure organized in a head to tail orientation in the dimer. Each subunit contains four antiparallel β strands tightened with a central cystine-knot motif from which three hairpin loops are deployed so that loops 1 and 3 from one subunit are intertwined with loop 2 of the other subunit. The determining knot motif involves six cysteine residues from each subunit (Figure 4). Four of them bridge β2 and β4 strands with two disulphide bonds forming an eight-residue ring through which penetrates a third disulphide bond linking the two other cysteine residues from the β1 and β3 strands. The α subunits contain a total of 10 cysteine residues, the two additional pairs linking the β1 to β2 and β3 to β4 strands tying the amino-and carboxy-termini to the core molecule. The β subunits have twelve cysteine residues. In addition to those involved in the knot, two of them form a disulphide bridge linking together the tips of loop 1 and loop 3 and two others, seven amino acids apart from each other, are involved in an intra-chain bonding located at the end of the β4 strand. The last two cysteine residues form a disulphide bridge between loop 1 and the Cterminal extremity that constitutes the buckle of the "fastening belt" that wraps the carboxyend of the β subunit around the α subunit loop 2. This latter structure is of crucial importance for maintaining the stability of the dimer at the low concentrations encountered in the peripheral circulation [START_REF] Alvarez | Comparative structure analyses of cystine knot-containing molecules with eight aminoacyl ring including glycoprotein hormones (GPH) alpha and beta subunits and GPH-related A2 (GPA2) and B5 (GPB5) molecules[END_REF]888).

α subunits

The α subunit is globally well conserved across vertebrates, a feature that is expected since a mammalian α subunit is able to associate with a teleost LHβ subunit to produce a heterodimer that retains most of the biological activity of the native teleost LH [START_REF] Burzawa-Gérard | Formation d'une molecule hybride douée d'une activité gonadotrope sur la Grenouille, à partir de la sous-unité α de l'hormone lutéinisante bovine et d'une sous-unité de l'hormone gonadotrope d'un Poisson téléostéen[END_REF]201). Such stability in structure probably results from the constraints imposed on the α subunit that has to efficiently associate with three different β subunits. The α subunits show alternate variable and conserved regions. The variable regions, where insertions/deletions are encountered, are located at the level of loop 1 and loop 3 as well as in the amino-terminal end of the protein.

On the contrary, the most conserved regions lie in β2, β3 and β4 strands and in loop 2. Great apes α subunit sequences are characterized by a 4-amino acid-long deletion in the aminoterminal end, at an intron-splicing site. Some teleostean or chondrostean sequences also show deletions at this site. Surprisingly, mutations of cysteine codons occur in some sequences. This is particularly the case in hagfish (Epatretus atami) where cysteines C2 and C4 are replaced by an arginine and a tyrosine, respectively. C2 is usually involved in the disulphide bridge with C7 that is part of the cysteine knot motif whereas C4 bridges with C1 to move β1 and β2 strands closer to each other (Figure 4). There is only one clone identified and sequenced in hagfish (819), so these apparent mutations might result from artefacts in the cloning or sequencing process. Nevertheless, a different assignment of the cysteine residues may be operating in this subunit with C1 replacing C2 in the bonding with C7 and the absence of bonding between β1 and β2 strands. Substitutions in cysteine residues are also observed in binding and signal transduction, and eventually on metabolic clearance of gonadotropins (271). Since three species at least out of this taxonomic group share this substitution, a compensatory mechanism should occur for these gonadotropins to assemble and elicit full biological activity.

LHβ subunits

LHβ subunits are 112-121 amino acid-long, with the exception of equine LHβ where a 10 nucleotide-long deletion induces a shift in the reading frame leading to an extension of the carboxy-terminal end in very much the same as for hCGβ (702). The lamprey gonadotropin β subunit (Petromyzon marinus -AY730276.1) is also extended at the carboxy-terminal side. If it is an ancestral characteristic, it has not been conserved in the hagfish (Eptatretus atami -AB546741.1), another cyclostome species. In comparison to the α subunit, there are no major insertions/deletions within the mature proteins apart for single or two amino acid-long deletion events in some species, occurring in the region of loop 2. The degree of conservation at the amino acid level is lower than in the α subunit. In addition to the twelve cysteine residues, conserved amino acids are found mostly within the β strands but also in the loops that seem to be more constrained than in the α subunit. LH and TSHβ subunits usually have one glycosylation site conservatively located in the β1 and the β2 strand, respectively, whereas FSHβ subunits have both of them. One glycosylation site is actually found in a conserved position in almost all LHβ subunits. It is to be noted that, in the spotted green pufferfish (Tetraodon nigroviridis -CR706772.2) and in the fugu Takifugu rubripes -XM_003963794.2), two related species, the unique glycosylation site is displaced to the carboxy-terminal end, between C10 and C11, two cysteine residues that are linked by a disulphide bridge. The zebrafish (Danio rerio -BC162111.1) LHβ subunit has a second site also at this position. Two glycosylation sites are also found in LHβ subunits in primates except in human. The two sites are located as in FSHβ subunits. Remarkably, the gonadotropin β subunit of cyclostomes, the most basal extant vertebrate species, is provided with the same two glycosylation sites. It is not known whether cyclostomes have only one or two pituitary gonadotropins. All TSHβ subunits have two additional amino acids inserted in loop 2 (467) so that the hormone identified in cyclostome that do not have these two additional amino acids most likely belongs to the gonadotropin lineage. It is not known if this GTH is homologous to LH or FSH or is ancestral to LH and FSH, hence the naming GTH for gonadotropic hormone (739,741,819). A third potential glycosylation site is found in the lamprey GTHβ subunits in their specific carboxyl extension.

CGβ subunit

The primate CGβ subunit genes arose from a duplication of the LHβ subunit gene just before the divergence between New World and Old World Monkeys (see 3.3 Origin and evolution of gonadotropins). These sequences are characterized by a frame shift in the coding sequence due to a single nucleotide deletion, 8 codons before the LHβ stop codon. This event generated a carboxyl extension of the encoded protein including several serine residues that are Oglycosylated in trophoblast cells. One of the consequences of this higher glycosylation level is the higher half-life of hCG in the blood when compared to hLH (112).

Equine CGβ subunits are encoded by the LHβ subunit gene expressed in the trophoblast. Surprisingly, a similar carboxyl extension phenomenon occurred in equidae albeit due to a different mechanism. In equidae, a ten nucleotide-long deletion occurred, leading to the same frame shift as in primates (702).

FSHβ subunit

The less conserved subunit is the β subunit of FSH. This is mainly due to their high evolutionary rate in the teleost lineage (627). Up to twelve amino acid residues are deleted in the most derived teleosts, the acanthomorphes, essentially in the loop regions. The most spectacular feature of the teleost FSHβ subunits is the rearrangement of the cysteine residues.

Although conserved in most basal teleosts including ostariophyses (carp and catfish related species), cysteine C3, which is involved in the latch of the seatbelt loop with C12, is then lost.

The seatbelt loop is determinant for the ability of the dimer to keep associated once diluted in the general circulation. Teleosts have developed alternative means to ensure the seatbelt to be fastened. In more recently emerged taxonomic groups (clupeocephala), an additional cysteine (which will be referred to as C0) is found at the amino-terminal end that is extended to the left and includes amino acids aligned to the signal peptide in other taxonomic groups (elopomorphes (341); salmonids (758, 761); percomorphes (225, 226, 373, 553, 866)). It was found by mutating the hCG β subunit so as to reproduce this teleost-type cysteine pattern that the seatbelt could be latched by a disulphide bridge between C0 and C12 (888). In cyprinodontiformes, the mature sequence after cleavage of the signal peptide does not include C0 (709). Instead, another cysteine residue is found either two amino acids downstream of the usual C3 position or just following C5, and it is likely that these subunits use the natural gonadotropin β subunit folding pattern. The cleavage site of the signal peptide has not been characterized so far in ostariophyses. If the mature protein includes C0, their sequence would totalise 13 cysteine residues. Another striking feature in FSHβ subunits is the more flexible position and number of glycosylation sites. FSHβ subunits usually have two glycosylation sites. The one on the β1 strand is generally well conserved except in some teleosts. The other site is absent or displaced to variable regions in most teleost species. In an extreme case, the Atlantic halibut (AJ417768), the FSHβ subunit is deprived of any glycosylation site. At the opposite, a third site is occasionally found in some sharks, teleosts, turtles, birds and crocodiles. The unique pattern of cysteine arrangements or glycosylation states of teleost FSHs offers remarkable examples to investigate structure-function relationships. It is to be noted that most of these studies have been performed on mammalian hormones expressed in mammalian cells cultured at 37°C and thus, far from the low temperature at which most teleost gonadotropin assemble and act.

Origin and evolution of gonadotropins

Recent discovery of additional members of GPH family in mammals

In search for ligands for orphan G-protein-coupled receptors in the human genome, Hsu and his colleagues identified two new glycoproteins, also present in other vertebrate genomes, that share numerous characteristics with the glycoprotein hormone subunits (293). They were called GPA2 (GPHA2) and GPB5 (GPHB5) as for the second glycoprotein hormone related α subunit and the fifth glycoprotein hormone related β subunit. GPA2 and GPB5 are able to associate into heterodimer and the heterodimer is able to stimulate the TSH receptor but not the gonadotropin receptors (523). The heterodimer was therefore named thyrostimulin.

Ancient origin of GPA2/GPB5 before the emergence of vertebrates

These glycoproteins, which are found in most bilateria (293,581,640,645,663), are now referred to as GPA and GPB in invertebrates that lack the classical glycoprotein hormone subunits [START_REF] Campbell | Piecing together evolution of the vertebrate endocrine system[END_REF]. In most investigated invertebrates, the genes encoding GPA and GPB are located close to each other without intervening genes (662), suggesting a functional or regulatory link between them. A leucine-rich repeat-containing receptor related to the glycoprotein hormone receptors (279, 437) was also identified in several invertebrate species (645). The fly receptor (LGR1) binds and is activated by the fly GPA/GPB heterodimer (749).

Interestingly, in the parasitic wasp Nasonia (266), the leech Helobdella (832) and the myriapode Strigamia (833), three species that lack GPA and GPB, the homologous receptor is Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019. also absent. Altogether, these data strongly suggest that the vertebrate glycoprotein hormone α and β subunits derive from a duplication of GPA and GPB, respectively, early after the emergence of vertebrates.

A limited role for vertebrate GPA2/GPB5 in reproduction

No consensus role for GPA and GPB in invertebrates have been proposed to date even if they may have been involved in specific functions in different species (640). In vertebrates, few data are yet available. Like GPHα, GPA2 harbours two glycosylation sites, the position of the one just after loop 2 being conserved. The other one is located on the β1 (by analogy with GPHα) strand. GPA2 lacks the cysteine residues involved in the bonding between β1 and β2 strands. It contains, in addition to the six residues composing the cystine-knot motif, two cysteine residues that are believed to form a disulphide bridge between loops 1 and 3. These loops appear longer than in GPHα. GPB5 is encoded by two exons with the same intron/exon splicing site as for GPHβ subunits. It harbours only one glycosylation site, located on the β3 strand, just following the cysteine knot motif. The main difference between the GPB5 and GPHβ subunits is the absence of the carboxy extension that constitutes the seat belt. As mentioned earlier, this seat belt is essential for the stability of the dimer so it is believed that a GPA2/GPB5 dimeric structure may not be maintained once diluted into the general circulation [START_REF] Alvarez | Comparative structure analyses of cystine knot-containing molecules with eight aminoacyl ring including glycoprotein hormones (GPH) alpha and beta subunits and GPH-related A2 (GPA2) and B5 (GPB5) molecules[END_REF]. The thyrostimulin naming of the GPA2/GPB5 dimer is based on the ability of the recombinant dimer to stimulate the TSH receptor but not gonadotropin receptors (523,552). It is further supported by the hyperthyroid phenotype observed in mice chronically injected with the recombinant dimer (552) and in mice ubiquitously overexpressing GPB5 (443). In the latter case, the thyrotropic effect was attributed to the dimer formed by the overexpressed GPB5 with the GPA2 naturally expressed in the thyroid to activate the TSH receptor. However, the thyrostimulin concept is not supported by the absence of obvious Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] thyroid phenotypes in GPB5 knocked-out mice (443, 552) except for a transient hypothyroxinemia in juveniles (907). Surprisingly, no GPA2-knocked-out mice have been described. The GPA2/GPB5 dimer is 10 to 20 times more active that TSH in stimulating TSH receptor (552). Taking into account the wide variety of tissues expressing GPA2 and/or GPB5 (293,520,523,552) and the TSH receptor (874), it is conceivable that the GPA2/GPB5 dimer may act as a local activator of TSH receptor. However, numerous tissues do not seem to coexpress GPA2 and GPB5 so that, as for the free α and hCGβ subunits, other modes of action as monomer or homodimer must be explored for GPA2 and GPB5. In any case, no abnomalities in fertility were mentioned in GPB5 knocked-out mice (443,552,906,907) so that a major role of the GPA2/GPB5 dimer or of GPB5 by itself in the control of reproduction is very unlikely.

Evolution of the GPH family in vertebrates

Taking advantage of the availability of sequenced genomes from species of phylogenetical significance, comparative synteny analysis between amphioxus (a pre-vertebrate chordate) and vertebrate glycoprotein hormone subunit loci allowed the reconstruction of their evolutionary history in vertebrates (467,663). A first local duplication of a tandemly organized GPA and GPB locus occurred just before the radiation of vertebrates and the emergence of cyclostomes, giving rise to the vertebrate forms of GPA and GPB (GPA2 and GPB5) and to the ancestral glycoprotein hormone (ancGPH) α and β subunits (Figure 5). The ancgphα gene was maintained close to gpa2-gpb5 whereas the ancgphβ gene was translocated soon after the duplication. After the first round of WGD (1R), one copy each of gpa2 and gphα was lost from one of the duplicated gpa2-gphα-gpb5 loci, leaving two copies of gpb5, i.e. gpb5a in the remaining gpa2-gphα locus and gpb5b. After the second WGD (2R), only one copy of the duplicated gpb5b was retained. From the duplicated gpa2-gpb5a-gphα locus, one copy of the duplicated gphα and one copy of the duplicated gpa2-gpb5a were lost, leaving a single gphα encoding gene and the remaining single copies of the tandemly organized gpa2 and gpb5a. These two genes were kept in tandem in teleosts (663) and in the Coelacanth (Ensembl scaffold JH127632; unpublished data). gpb5a was lost in tetrapods that only retained gpb5b. The ancestral form of gphβ that was somehow parted from its original environment soon after the original, local duplication was duplicated at the 1R giving rise to an ancestral the gonadotropin β subunit gene (ancgthβ) and to an ancestral TSHβ subunit gene (anctshβ) (Figure 5). The 2R duplicated the ancgthβ to generate lhβ and fshβ genes. One of the duplicated copy of the anctshβ gene (encoding TSHβ2) was retained in chondrichthyes and in lungfish and coelacanth but was lost before the radiations of teleosts and tetrapods (467). Of note, after the Teleost-specific WGD (3R), of all duplicated gph genes only the duplicated tshβ1 gene was maintained (encoding TSHβ3 or TSHβ1b according to a recent nomenclature), all other duplicated glycoprotein hormone subunit genes being lost (467, 663).

As mentioned earlier, two copies of GPHα subunit-encoding genes may have been generated in some teleost species, resulting from recent, specific tetraploidization events. While a tandem duplication was at the origin of the glycoprotein hormone family in vertebrates, the most recently appeared glycoprotein hormone, CG, was also generated by a tandem duplication that occurred during the radiation of primates, just before the divergence between New and Old World monkeys, some 35 to 55 Million years ago (272,460).

Subsequent gene duplications led to a rising number of CGβ duplicates, that are not all functional (in human, 4 out of 6 CGβ genes are functional), up to about 50 copies in gorilla (169). The New World monkeys have only one CGβ and one LHβ subunit gene. Surprisingly, in the marmoset and probably in all New World monkeys, the LHβ gene has lost its pituitary functionality, and it is the CGβ gene that is expressed in the pituitary and in the placenta from specific promoters (514). The first duplication event probably affected only the LHβ gene but subsequent duplications also concerned the neurotrophin NTF4 gene (also called NTF5 or NTF6) although only one copy retained its functionality. Surprisingly, phylogenetic analysis of LHβ and CGβ transcripts showed that CGβ sequences tend to group with the LHβ sequence from the same species instead of with CGβ sequences from closely related species. This phenomenon was shown to be due to gene conversion i.e. nonreciprocal transfer of sequence information, where the LHβ gene sequence and notably its first and second exons act as the parent for cgβ genes conversion (460).

Origin and evolution of GnRH, brain conductor of reproduction in vertebrates

1. Introduction

In the late 1920s, once the involvement of the pituitary in the processes of reproduction was demonstrated, systematic investigations were initiated to decipher the link between the hypothalamus and pituitary gonadotropin secretion (491,614). Harris was the first to propose the hypothesis of neurohumoral regulation of gonadotropin secretion (192). The question that remained to be resolved was how information perceived in the CNS would be communicated to the pituitary gland. In the early 1960s, several investigators reported, in crude hypothalamic extracts, the existence of substances that specifically stimulated the secretion of luteinizing hormone (LH) or folliculo-stimulating hormone (FSH), and that were probably polypeptides (367). It was concluded therefore that the hypothalamus regulates the release of LH and FSH by means of two releasing hormones (LH-RH and FSH-RH), transported to the anterior pituitary via the hypothalamic portal circulation. From that moment, several teams devoted their efforts to the isolation and identification of LH-and FSH-releasing hormones. The isolation of the single substance able to stimulate the synthesis and secretion of both gonadotropins was independently achieved in 1971 from porcine and ovine brain by the groups of Schally (465) and Guillemin [START_REF] Amoss | Purification, amino acid composition and N-terminus of the hypothalamic luteinizing hormone releasing factor (LRF) of ovine origin[END_REF][START_REF] Burgus | Molecular structure of the hypothalamic factor (LRF) of ovine origin monitoring the secretion of pituitary gonadotropic hormone of luteinization (LH)[END_REF], respectively. It was a decapeptide that was Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] initially termed LH-releasing hormone (LHRH) or LH-releasing factor (LRF), but the molecule is now generally referred to as gonadotropin-releasing hormone (GnRH). For this seminal discovery, Schally and Guillemin were awarded the Nobel Prize in Physiology or Medicine in 1977.

Origin and evolution of GnRH

GnRH in mammals

The first GnRH form isolated from pig and sheep is an amidated decapeptide with the sequence pQHWSYGLSPGamide [START_REF] Burgus | Molecular structure of the hypothalamic factor (LRF) of ovine origin monitoring the secretion of pituitary gonadotropic hormone of luteinization (LH)[END_REF]465). This sequence is identical in almost all mammalian species investigated so far (556). As other neuropeptides, GnRH is synthesized as part of a larger precursor molecule called pre-proGnRH. The full-length cDNA encoding this precursor was initially cloned from a human placental library (687). In human, pre-proGnRH is a protein of 92 amino acids that consists of the decapeptide, extended at the N-terminus by a signal peptide, and at the carboxy-terminus by a Gly-Lys-Arg sequence necessary for enzymatic cleavage and carboxy-terminal amidation of GnRH. The 56 aa-residue sequence located in the C-terminal region of the precursor is called the GnRH-associated peptide (GAP). The architecture of pre-proGnRH is conserved in other mammals.

The mammalian GnRH gene is composed of four exons and three introns (688). Exon 1 contains a part of the 5'-UTR. Exon 2 encodes the rest of the 5'-UTR, the signal peptide, the GnRH decapeptide, the amidation/proteolytic processing motif and the N-terminal part of the GAP. Exon 3 encodes the central portion of the GAP. Exon 4 encodes the C-terminal part of the GAP along with the 3'-UTR.

Immunofluorescence and immunohistochemical studies using specific antibodies revealed that GnRH is primarily localized in neurons located in the hypothalamus, particularly in the arcuate-median eminence region and the preoptic area [START_REF] Barry | LRF producing cells of the mammalian hypothalamus -A fluorescent antibody study[END_REF]403). In the median eminence, GnRH nerve terminals secrete directly into portal capillaries. The peptide is then delivered by the portal circulation to the adenohypophysial gonadotrope cells (614). An important feature of the secretory activity of GnRH neurons is its pulsatile nature [START_REF] Belchetz | Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone[END_REF]. The frequency and amplitude of secretory episodes are essential for the release as well as the synthesis of LH and FSH by gonadotrope cells (784).

It was shown that GnRH neurons arise from the nasal placode and migrate to their target regions in the hypothalamus during development (682, 881); for review:(880)) This finding is in agreement with the observations that humans deficient in GnRH also lack their sense of smell and with studies showing a loss of GnRH cells in animals with olfactory placode ablation (871, 880).

In 1994 was reported, for the first time in mammals, the occurrence of a second GnRH gene (347). Details regarding this second gene will be provided in the next section since it encodes a peptide whose sequence was already described in chicken since 1984 (500).

GnRH in other vertebrates: contribution to the discovery of multiple GnRHs

For a long time after it was discovered, GnRH was thought to have an invariant sequence because all mammalian peptides that were characterized were identical (643). This view was invalidated in 1982 when the first GnRH variant, containing the substitution Arg 8 Gln, was isolated from chicken hypothalami (364,365,498,499). Several other molecular isoforms were subsequently identified through peptide purification, cDNA cloning, and more recently data mining. They were primarily found in teleosts, but also in amphibians, elasmobranches and cyclostomes, and even in mammals (for review: (556)). They were generally named according to the species in which they were initially isolated. However, a given form found in a particular species or group can exhibit a much wider distribution, making this nomenclature particularly confusing. For example, salmon GnRH (sGnRH) (703) is present in many other teleost species, including medaka and zebrafish (381,555). Likewise, the mammalian form of GnRH (mGnRH) is also found in frogs (127, 269) and fishes (228,558) but not in the guinea pig (323).

In 1984, the occurrence of a second GnRH was demonstrated in the chicken, called chicken GnRH-II (cGnRH-II) in addition to cGnRH-I (500). Since then, it became evident that almost all vertebrate species are able to produce more than one GnRH form, each encoded by a peculiar gene (for review: (556)): two in most of them, including human (868) and even three, notably in teleosts (870) but also in lampreys (349,704,715,737,757). Very interestingly, cGnRH-IIs is present in all gnathostomes with exactly the same structure. As a result, in species that express two GnRH forms, the cGnRH-II variant is systematically present in combination with a second one which corresponds to mGnRH in most mammals (870), some amphibians (127) and fishes (228), or cGnRH-I in birds (498, 500) and reptiles (436). In teleost species possessing three forms, cGnRH-II is often associated with the sGnRH variant, plus a third form whose structure is more variable (619).

The peptides belonging to the GnRH family share several characteristics: (i) They all are decapeptides with residues 1, 4, 9 and 10 perfectly conserved as well as modified amino-(pGlu) and carboxy-terminus (NH 2 ) (248) (Table 1). (ii) They originate from preproGnRH precursors that exhibit the same features as those of mammals ( 248). (iii) The general organization of their genes is similar (188), suggesting they all share a common ancestral gene.

In the brain of species containing several GnRH forms, each variant exhibits a peculiar distribution. In gnathostomes, three major GnRH neuronal systems were recognized (163).

The first one, called the ventral forebrain GnRH system, is composed of neurons mainly located in the preoptic area of the hypothalamus and projecting toward gonadotrope cells in the pituitary. The GnRH molecular form synthesized by these neurons is variable depending Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] on the species: e.g. mGnRH, cGnRH-I, frog GnRH (fGnRH), sea bream GnRH (sbGnRH) or guinea pig GnRH (gpGnRH). Functionally, this peptide corresponds to the hypophysiotropic GnRH form initially characterized by Schally and Guillemin. The second GnRH system, called midbrain GnRH system, is composed of neurons located in the midbrain tegmentum near the third ventricle. These neurons project throughout the brain, especially in the midbrain and hindbrain, but also in the pituitary in some teleost and amphibian species. They produce the cGnRH-II form. The third system, called the terminal nerve GnRH system, has so far been identified only in teleosts. Neurons of this system are mainly located in the terminal nerve ganglion near the olfactory bulb, and project primarily to the telencephalon but also widely into the whole brain, including the retina and the olfactory epithelium. They specifically express the sGnRH variant (556). It is to note that, in some teleost species, cells from the hypothalamic GnRH systems and cells from the terminal nerve GnRH system clearly overlap in the forebrain (232,233,502). It was also shown that neurons from both systems share a common embryonic origin: they arise in the olfactory system and migrate into the forebrain [START_REF] Abraham | The zebrafish as a model system for forebrain GnRH neuronal development[END_REF][START_REF] Abraham | Targeted gonadotropin-releasing hormone-3 neuron ablation in zebrafish: Effects on neurogenesis, neuronal migration, and reproduction[END_REF]233,234,557,869). 4.2.3. Evolution of GnRH genes in vertebrates: impact of WGD Because GnRHs are short peptides, their evolutionary relationship was difficult to establish solely on the basis of their primary structure (337). In 1998, a phylogenetic analysis of GnRH prepro-hormones from 23 species of bony fish and mammals revealed the existence of three evolutionarily distinct GnRH groups, named GnRH1, GnRH2 and GnRH3 (869). These three groups globally coincide with the three GnRH forms identified on the basis of their location in the brain: releasing form localized to the hypothalamus (GnRH1), form previously localized solely to midbrain nuclei (GnRH2), and form localized to the telencephalon in teleosts (GnRH3) (188).

Subsequent phylogenetic studies including newly discovered sequences confirmed this categorization, which is now widely accepted and is at the basis of the current nomenclature (248,337,556). The occurrence of three GnRH paralogous genes is also supported by synteny analysis (360,381,555,643,644,790) since each GnRH gene is positioned in genomic regions containing common neighbors across teleost and tetrapod species.

GnRH1 and GnRH2 are clearly two "old" genes since the peptides they encode exhibit a very well conserved structure among gnathostomes. In contrast, GnRH3 has long been considered as a teleost-specific gene, suggesting a more recent emergence, possibly through the teleostspecific whole-genome duplication (3R) (248,337,556). However, this hypothesis was rejected when it appeared that genes surrounding GnRH3 in teleosts are also present in tetrapods (360,381,555,790). The view that GnRH3 arose by an ancient duplication before the teleost-tetrapod split was recently confirmed by the finding of a GnRH3 ortholog in coelacanth and several species of elasmobranches (219,644,903).

In lamprey, three members of the GnRH family of neuropeptides have been identified, named lamprey GnRH-I (lGnRH-I), lGnRH-II and lGnRH-III (349,704,715,737,757). The precise relationship between lamprey peptides and the three subtypes of GnRH in other vertebrates was difficult to resolve. Phylogenetic analysis initially led Sower et al. (2009) (740) to propose that lGnRH-II may represent a vertebrate GnRH2 ancestral form and to classify lGnRH-I and lGnRH-II in a fourth group of vertebrate GnRH peptides. Once again, both assumptions were refuted by synteny analysis showing that lGnRH-II is a GnRH2 ortholog while lGnRHI and lGnRH-III are two copies of GnRH3 that probably arose through tandem duplication (143,252,644,725). It should be noted that the presence of GnRH was suggested in the hagfish hypothalamus by both radioimmunoassay and immunohistochemistry, but the identity of the peptide remains to be determined (541). It is now well accepted that the three GnRH paralogs appeared together through the 2R. In strong support of this view is the observation in the genome of many species that GnRH1, GnRH2 and GnRH3 loci, in addition to a fourth locus without GnRH but sharing homologous neighboring genes, are part of a same tetra-paralogon (360,790,903). Moreover, a GnRHlike gene recently characterized in amphioxus is positioned in a locus surrounded by syntenic homologs of the human GnRH tetra-paralogon (642). Taken together, these data suggest that four GnRH paralogs, including a putative GnRH4, were present in the last common vertebrate ancestor (360, 790) (Figure 6).

After 2R, the history of the GnRH family was driven, across vertebrate evolution, by multiple and independent gene loss events, leading to the diversity of GnRH currently known.

The GnRH1 gene occurs is all gnathostomes but not in cyclostomes, suggesting gene loss specifically in this latter lineage. The GnRH2 gene is currently the most represented GnRH gene in living vertebrates. No GnRH3 gene has so far been isolated from any tetrapod, while it is present in several groups of fish. It thus appears that this gene was likely deleted during the early evolution of the tetrapod lineage. Finally, the putative GnRH4 gene probably disappeared shortly after 2R without leaving any trace in current species (Figure 6).

Apart from these general considerations, additional species-, genus-or family-specific losses of a GnRH form subsequently occurred independently in different vertebrate lineages. For example, some teleosts lost GnRH1 (salmon, trout, goldfish, zebrafish, arowana) or GnRH3 (eel, catfish, butterfly fish). In elephant shark, only GnRH1 and GnRH2, but not GnRH3, were identified (536, 644). Also, certain mammalian species lost GnRH2 (rat, mice, cattle, sheep, chimpanzee), and thus now possess only GnRH1 (746). It is to note that no effect of the 3R can be recorded on the current number of GnRH genes in teleosts, suggesting massive gene losses after 3R. In contrast, two GnRH3 are present in sockeye salmon [START_REF] Ashihara | Two differing precursor genes for the salmon-type gonadotropin-releasing hormone exist in salmonids[END_REF], probably due to the salmon-specific whole-genome duplication (4R) (420), while two tandemly arranged GnRH1 exist in elephant shark (219) (Figure 6).

The detailed evolutionary relationship between the three GnRH paralogs is still not completely understood. Phylogenetic analysis shows that GnRH1 and GnRH3 sequences group into the same clade, suggesting they share a common ancestor (248,349,800).

Moreover, in teleosts, GnRH1 and GnRH3 neuronal systems exhibit striking similarities regarding both their embryonic origin and their distribution in the brain (337,556). Taken together, these data support the notion that 1R generated on the one hand the GnRH1-GnRH3 ancestor and on the other hand the GnRH2-GnRH4 ancestor. Although appealing, this scenario remains to be confirmed.

Origin and evolution of GnRH receptors

GnRH-R in mammals

GnRH receptors (GnRH-R) were initially characterized in the pituitary and several other tissues such as the brain, placenta and gonads, as specific binding sites with high affinity for mGnRH1 and its potent agonist or antagonist analogs (747). Some immortalized cell lines derived from neoplastic tissues also proved to be an important source of GnRH-R (747). One of them, the mouse pituitary αT3 gonadotrope cell line, led to the molecular isolation of the first GnRH receptor sequence, by expression screening for electrophysiological (809) or calcium responses (634) in Xenopus oocytes. This sequence provided the basis for the cloning of GnRH-R in several other species (506,686).

GnRH-R is mainly expressed in gonadotrope cells of the pituitary, in agreement with its role in the synthesis and release of gonadotropins, but it is also present in extra-pituitary tissues including the brain (320), placenta, gonads, prostate, uterus and breast (108, 637). GnRH-R is also expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019. cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. Activation of GnRH-R was shown to inhibit proliferation of transformed cells making this receptor a therapeutic target for direct action of GnRH analogues on certain proliferating cells (422,450).

Analysis of the primary sequence identifies the GnRH receptor as a member of the rhodopsin β-like G protein-coupled receptor (GPCR) family, which contains a characteristic seven transmembrane (TM)-domain structure (686). Unlike most GPCRs, which are intronless, the GnRH-R gene is composed of three exons and two introns (181).

A hallmark feature of the mammalian GnRH-R is the absence of a cytoplasmic carboxyterminal domain, which is unique among GPCRs (686). As a result, this receptor is resistant to rapid desensitization and internalizes very slowly (142, 597). The extracellular loops (EC) and superficial regions of the transmembrane domains (TM) are responsible for receptorligand recognition and binding while the intracellular loops are involved in interacting with G proteins for signal transduction (196,490).

In gonadotrope cells and gonadotrope-lineage cells, activation of the GnRH receptor stimulates a variety of intracellular signalling pathways [START_REF] Chang | Comparative aspects of GnRH-Stimulated signal transduction in the vertebrate pituitary -Contributions from teleost model systems[END_REF]525,600). However, it is generally accepted that the primary effect of GnRH binding to its receptor is the activation of phospholipase Cβ (PLCβ) through the G q/11 G protein and the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylgycerol (DAG) and inositol 1,4,5trisphosphate (IP3), which stimulates calcium release and activates protein kinase C (PKC) (247). These events lead to the synthesis and release of gonadotropins (747).

The presence of at least two GnRHs in most vertebrates, including mammals, suggested the existence of several cognate GnRH receptor subtypes (793). In support of this view, the occurrence of a second GnRH-R subtype (called GnRH-RII, as opposed to the first subtype now renamed GnRH-RI) was reported in non-human primates (488,530). It is noteworthy Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20,2019. that the GnRH-RII subtype is either partially or completely silenced in a number of mammalian species (human, chimpanzee, sheep, cow, rat, and mouse) (487,506,507).

A study carried out in marmoset showed that the type II GnRH receptor is more widely distributed than type I receptor (488). As expected, GnRH-RI exhibits greater sensitivity to the hypophysiotropic GnRH form, GnRH1, than to GnRH2. Conversely, the GnRH-RII shows greater sensitivity to GnRH2 than to GnRH1 (304,449,488).

GnRH-R in other vertebrates: contribution to the discovery of multiple GnRH-R

The first non-mammalian GnRH-R was isolated from catfish in 1997 (778). Remarkably, this receptor exhibits a 49-amino acid cytoplasmic carboxy terminal domain that is lacking in the mammalian receptors. Moreover, it possesses a much higher affinity for GnRH2 than for GnRH1. A number of subsequent studies described the cloning of GnRH receptors in several other species, including trout (447), Xenopus (794), and chicken (754). In some species, such as in goldfish (305), bullfrog (855) and sea bass (503), the coexistence of two, three and even five distinct GnRH-R subtypes was reported, respectively. Three GnRH-R were also characterized in lamprey (330,716). GnRH binding sites in GnRH-R type I and II forms are highly conserved but several amino acid residues in the second and fourth transmembrane domains confer selectivity toward GnRH1 and GnRH2 (122,205).

Interestingly, at both the structural and functional levels, non-mammalian GnRH receptors resemble more closely the mammalian type II receptors than the mammalian type I receptors.

Indeed, they all have a carboxy-terminal tail and a higher affinity (although sometimes modest) for GnRH2 than for GnRH1 (337). Moreover, in contrast to GnRH-RI, they show an Asp residue in transmembrane domain 2 that is conserved among members of the GPCR family. This Asp residue, that is replaced by an Asn residue in the mammalian GnRH-RI, is required for receptor activation (406,488). Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20,2019. As the mammalian GnRH-RII, non-mammalian GnRH receptors are expressed in numerous tissues, in particular in reproductive organs. In species possessing several GnRH-R subtypes, each receptor exhibits a distinct expression pattern (248). Both mammalian GnRH-RII and non-mammalian GnRH receptors generally couple to the Gq protein and therefore mediate the intracellular production of inositol phosphates [START_REF] Chang | Comparative aspects of GnRH-Stimulated signal transduction in the vertebrate pituitary -Contributions from teleost model systems[END_REF]337).

Evolution of GnRH-R genes in vertebrates: impact of WGD

The evolutionary relationship between vertebrate GnRH receptor is still obscur, making it difficult to propose a consensual nomenclature (see ( 613) for a detailed review of the different nomenclatures proposed over time). As mentioned above, vertebrate GnRH receptors were generally subdivided into two major types (I and II) on the basis of both their structural (presence or not of a C-terminal tail) and functional (selectivity to individual GnRH peptides) features. Type I GnRH-R only contains the mammalian « tail-less » sequences, while type II GnRH-R includes all remaining sequences, from both mammalian and non-mammalian species. Such a categorization is well supported by numerous phylogenetic analyses in which GnRH-RI and GnRH-RII sequences actually group into two separate major clades (302,613,643,644,690,776,873).

Until recently, GnRH-RI sequences were only found in mammals, suggesting that this receptor evolved after lineage-specific gene duplication in early mammals (337,643). This concept was eventually invalidated when sequences of GnRH-RI were found in coelacanth, elephant shark and little skate (644,690,873), indicating that the gnathostome ancestor already possessed a type I GnRH-R. Thus, functionally, the absence of the cytoplasmic tail in type GnRH-RI can no longer be viewed as an adaptation to mammalian physiology (873), as previously suggested by some authors (142,794). Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20,2019. In contrast to the type I clade, the type II clade is characterized by a wide heterogeneity, since it includes sequences from species of very diverse origins. This heterogeneity is reinforced by the fact that most of these species possess multiple type II receptor forms, e.g. three in lamprey, some teleosts and amphibians, and up to four in coelacanth. Hence, recent studies subdivided type II clade into two major clades, called IIa and IIb (613,644,873). IIa and IIb can be further split into three and two groups, respectively. The first type IIa GnRH-R clade contains all three of the lamprey GnRH-R sequences plus one of the coelacanth paralogs. The second type contains the mammalian type II GnRH-R plus one of the coelacanth paralogs, while the third type contains GnRH-R sequences from teleosts, coelacanth, amphibians, reptiles and birds. The first type IIb clade also contains GnRH-R sequences from teleosts, coelacanth, amphibians, reptiles and birds, while the second type is exclusively composed of teleost sequences. It is noteworthy that the two IIb subtypes are not discriminated in the Williams's study.

At first sight, the logic of this breakdown is not obvious. Indeed, phylogenetic analyses, alone, are not perfectly suitable to explain the origin of the different GnRH receptor subtypes, and their evolutionary relationships. Recently, several studies have tried to revisit the history of the GnRH-R family in light of the 2R theory (360,644,690). For instance, Roch et al. (2014) proposed that all three major GnRH receptor subtypes (types I, IIa and IIb) were already present in the vertebrate ancestor before 2R (644). These three receptors would have been the products of two successive events of tandem duplication.

According to their model, 2R theorically led to the generation of 12 GnRH-R subtypes (Figure 7). However, due to multiple gene losses, only six of them were preserved.

Thereafter, further losses could occur in the different vertebrate lineages, eventually leading to the current situation. This model is in good agreement with phylogenetic data, which identify a total of six GnRH-R subtypes. However, on the basis of practically the same data, [START_REF] Williams | Hypothalamic amines and the release of gonadotrophins and other anterior pituitary hormones[END_REF] propose a totally different scenario, in which only three GnRH-R genes were present in the gnathostome ancestor (873). By constrast, they argue that the current data do not resolve the number of GnRH receptors in the common ancestor of vertebrates and the actual impact of 2R.

Taken together, this information shows that further studies, combining both phylogenetic and syntenic data, will be needed to fully understand the evolution of the GnRH-R family in vertebrates.

Origin of the GnRH system before the emergence of vertebrates

In order to gain more insight into the origin of GnRH, intensive efforts have been made to hunt out GnRH-related peptides in phyla other than vertebrates.

GnRH and GnRH-R in non-vertebrate chordates

The first molecular evidence that GnRH occurs outside vertebrates was provided by the characterization of multiple GnRH-like peptides in tunicates, encoded by one or two different genes, depending on the species [START_REF] Adams | Six novel gonadotropin-releasing hormones are encoded as triplets on each of two genes in the protochordate, Ciona intestinalis[END_REF]264,618,644). In several species examined, such as Ciona sp. or Haloclynthia sp. [START_REF] Adams | Six novel gonadotropin-releasing hormones are encoded as triplets on each of two genes in the protochordate, Ciona intestinalis[END_REF]264), pre-proGnRHs are multifunctional precursors, each containing the sequence of two to three tandemly arranged peptides. However, despite the unique organizaton of their precursor, almost all tunicate GnRH forms identified so far are decapeptides including the six invariant amino acids, in positions 1-4, 9 and 10, found in vertebrates (644) (Table 1). It is noteworthy that the occurrence of both mGnRH and cGnRH-I reported by Di Fiore et al. (2000) (193) in Ciona could not be confirmed [START_REF] Adams | Six novel gonadotropin-releasing hormones are encoded as triplets on each of two genes in the protochordate, Ciona intestinalis[END_REF].

Search of the Ciona genome also led to the identification of four GnRH receptors (775). All these receptors possess a C-terminal tail similar to vertebrate type II GnRH-R, as well as several other structural features shared with vertebrate GnRH-Rs (643). At the functional level, only one tunicate receptor is able to activate the G q/11 pathway and to trigger IP3 accumulation, while the three others provoke an increase of cyclic AMP formation through stimulation of G s (775). At the evolutionary level, the four Ciona GnRH receptors cluster into a single clade at the root of the vertebrate GnRH-R one (644). Taken together, these data demonstrate unequivocally the existence in tunicates of a GnRH system homologous to that in vertebrates.

The occurrence of a functional GnRH system was also reported in amphioxus. However, the first Blast searches of the amphioxus genome allowed the identification of only GnRH-like receptor but not peptide sequences (776). Of the four amphioxus GnRH-R sequences found, only two, GnRH-R1 and GnRH-R2, cluster as expected, at the root of the chordate GnRH-R tree (642, 644). In constrat, the two others, GnRH-R3 and GnRH-R4, appear much more distant and do not group with chordate GnRH-R sequences (see below for more details).

Nevertheless, the four amphioxus GnRH-R genes are positioned in the same locus surrounded by syntenic homologs of the vertebrate GnRH-R paralogon (642).

In 2009, a peptide with GnRH sequence identical to mammalian GnRH1 was purified from amphioxus [START_REF] Chambery | Characterization and putative role of a type 1 gonadotropin-releasing hormone in the cephalochordate amphioxus[END_REF] but this result proved to be artifactual (642). The occurrence of a genuine amphioxus GnRH-like gene was reported only five years later by using a more sensitive search methodology with hidden Markov models (642). The GnRH identity of this gene was confirmed by synteny analysis. However, the GnRH-like peptide encoded by this gene exhibits a very atypical structure, pQILCARAFTYTHTWamide, since of its 14 amino acids (aa) (and not 10), 3 only are conserved at positions 1, 5, and 7 with vertebrate GnRH2 residues (Table 1). It has been proposed that the amphioxus GnRH-like peptide may be cleaved to form a more active 7 aa-peptide (785). The amphioxus GnRH-like peptide acts as a ligand for amphioxus GnRH-R3 (642), but does not activate any of the three other amphioxus GnRH-R subtypes (642), indicating that the natural ligands of the latter receptors remain to be identified. It is to note that amphioxus GnRH-R1 and GnRHR-2 can be activated by vertebrate GnRH (642). Interestingly, a second GnRH-like peptide has been identified in the amphioxus genome (called GnRHv), but this peptide does not activate any of the four known amphioxus GnRH-R (642).

GnRH-like peptides and GnRH-R in other non-vertebrates

The first non-vertebrate GnRH-like molecule, at least clearly presented as such, was characterized in 2002 from a cephalopod mollusk, the common octopus (313). Octopus GnRH is a dodecapeptide that shares 7 residues with vertebrate GnRH2 from which it mainly differs by the insertion of two amino acids after position 1 (Table 1). The overall organization of the octopus GnRH precursor is the same as that of vertebrate pre-proGnRHs. Its cognate receptor was identified soon after and was demonstrated to have numerous similarities with chordate GnRH receptors (344).

Closely related peptides were subsequently identified in several other species of mollusks [START_REF] Bigot | Characterization of GnRH-related peptides from the Pacific oyster Crassostrea gigas[END_REF]831,912), annelids (832) and echinoderms (649, 695) (Table 1). All these newly identified peptides, together with the amphioxus GnRH-like peptide, were proposed to be classified as invertebrate GnRHs (invGnRHs), as opposed to vertebrate GnRHs (that also include the tunicate ones) (644). However, recent studies have shown that invGnRHs are probably not orthologous to GnRHs and should be renamed (see below) (613, 905).

Other GnRH-related peptides (AKH, CZR, ACP) and their receptors

In 1998, the occurrence of a receptor structurally related to vertebrate GnRH receptors was reported in Drosophila (267). Several years later, the ligand for this Drosophila GnRH-type receptor was characterized and identified as a member of the adipokinetic hormone (AKH) family (745). Such a result was totally unexpected since AKH has been well known for a long time in insects (470, 748) but without apparent relationship with GnRH. However, taking a closer look, GnRHs and AKHs appear to share the N-terminal pyro-Glu residue and the Cterminal amide plus various identical residues depending on the species, in particular a conserved Trp at the third last position. It thus appears reasonnable to consider peptides of the AKH family as possible GnRH homologs.

AKH is an insect peptide first isolated from the locust corpora cardiaca, a functional equivalent of the pituitary gland in insects ( 835), for its ability to mobilize lipids from the fat body during flight (748). Many different forms (8-10 residues) of this peptide hormone were subsequently described in various insect species, with even two or three gene copies in some of them (216) (Table 1). AKH is also known as the red pigment-concentrating hormone (RCPH) isolated several years earlier in crustaceans (189) The first RCPH receptor has been recently characterized from Daphnia (456).

In 1989, an AKH-like peptide was identified in the cockroach and named corazonin (CRZ, ''corazon" being the Spanish word for 'heart') on the basis of its cardioacceleratory properties (830). Although slightly larger in size (11 résidues), CRZ share several structural features with AKH (Table 1). Furthermore, their preprohormones have a similar organization indicating that the two neuropeptide precursor genes must have a common evolutionary origin (829). Like AKH, CRZ is expressed in neurosecretory neurons of the protocerebrum and transported to the storage lobes of the corpora cardiaca (622). The CRZ receptor was initally characterized in Drosophila by a reverse pharmacology strategy [START_REF] Cazzamali | Molecular cloning and functional expression of a Drosophila corazonin receptor[END_REF]582). Sequence analyses showed that CRZ, AKH and GnRH receptors are all evolutionarily related.

In 2006 [START_REF] Belmont | Identification of four evolutionarily related G protein-coupled receptors from the malaria mosquito Anopheles gambiae[END_REF] isolated from Anopheles a receptor with strong smilarities to the AKH receptor but which is activated neither by AKH nor by CRZ [START_REF] Belmont | Identification of four evolutionarily related G protein-coupled receptors from the malaria mosquito Anopheles gambiae[END_REF]. The natural ligand for this receptor was subsquently characterized as a new peptide called AKH/corazoninrelated peptide (ACP) due to its intermediate structural features with AKH and CRZ (261).

In all species examined so far, AKH, CRZ and ACP originate from precursors that exhibit the same overall organization as those of vertebrate GnRHs, with the mature peptide immediatly after the signal peptide. However, despite their structural similarities with other nonvertebrate GnRH-like receptors, the AKH receptors are specific for AKH and are not activated by ACP or CRZ. Similarly, the ACP receptors are specific for ACP and the CRZ receptors are specific for corazonin, showing that AKH, ACP and CRZ are three independent signaling systems (411).

For a long time, AKH, CRZ and ACP were thought to be confined to the arthopod clade, where they often (but not systematically) coexist in the same species (411). In 2009 the existence of an AKH-like peptide and its cognate receptor was reported in the nematode C. elegans (424), suggesting an older origin of the AKH signaling system. This notion was backed up soon later when it appeared that a functional AKH system is also present in mollusks (164,265,411), hemichordates (905) and echinoderms (785). Regarding the CRZ system, the same conclusion can be drawn from a recent study showing the presence of CRZ and its receptor in hemichordates and echinoderms (644, 785). In contrast, so far, ACP has been identified only in arthopods (905).

Evolutionary relationships between GnRH-and AKH-CRZ-ACP-like systems

The view that AKH, ACP, CRZ and GnRH peptides form a superfamily is generally well accepted (265,318,423,492,613,644,905). However, the precise relationships between CRZ, AKH, ACP and GnRH are poorly understood as illustrated by a very confused nomenclature (265,613,644,801,905). One of the major issues is whether AKH and CRZ neuropeptides can be both considered as orthologs to the vertebrate GnRH system.

Unfortunately, this issue is not really addressed by phylogenetic analyses. In contrast, it appears likely that the invGnRH group previoulsy defined by Roch (2014) ( 644) is not a monophyletic group (613, 801). It has thus been proposed to limit the name of GnRH exclusively to deuterostome GnRHs (613).

Regarding the receptors, the situation is also unclear. Phylogenetic analyses generally agree to recognize three majors clades (265,613,644,785). The first clade includes all chordate GnRH-Rs, except amphioxus GnRH-R3 and GnRH-R4, plus GnRH-R-like sequences from echinoderms, in other words most deuterostome GnRH-Rs. The second clade contains all arthropod CRZ-R sequences. It also encompasses amphioxus GnRH-R3 and GnRH-R4 plus some GnRH-R-like sequences from echinoderms and lophotrochozoans (annelids and mollusks). Surprisingly, among this second clade, are the octopus and Aplysia GnRH receptors, initially thought to belong to the GnRH-R group, as indicated by their name (344,348). Finally, the third clade encompasses all arthropod ACP-R plus AKH-R sequences from arthropods, nematodes and lophotrochozoans. Depending on the authors, different clusterings of these clades were proposed and formed the basis of two main evolutionary scenarios (654) (Figure 8). The first scenario states that an ancestral CRZ-R, which was conserved in the ambulacrarians (echinoderms and hemichordates) and the lophotrochozoans (annelids and mollusks), duplicated twice independently and thus generated two lineages: the first leading to CRZ-R and AKH-R, subsequently AKH-R generated artholopod ACP-R in ecdysozoans, and the second leading to GnRH-R in chordates (Figure 8A). The second scenario states that Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

GnRH-R and CRZ-R might have been arisen via gene duplication in a common ancestor of bilaterians, and that a second gene duplication of GnRH-R might have generated AKH-R and ACP-R during the divergence between lophotrochozoans and ecdysozoans (arthropods and nematods) (Figure 8B). The main difference between the two models is that, in the first one, AKH-R/ACP-R and GnRH-R are not orthologous since they arose independently while, in the second one, they are orthologous. In contrast, both models agree that the CRZ-R gene was probably lost in urochordates, vertebrates and nematodes.

The second scenario was particularly detailed by [START_REF] Zandawala | The evolution and nomenclature of GnRH-type and corazonin-type neuropeptide signaling systems[END_REF] who thus proposed to totally reconsider the classical nomenclature of the GnRH-and AKH-CRZ-ACP-like systems (905). According to these authors, who distinguish two major types of GnRH-like receptors, i.e. the (true) GnRH-R type and the CRZ-R type, the term AKH-R should be left out and replaced by GnRH-R in all bilaterian species, since AKH-R and GnRH-R are orthologous. Nevertheless, they suggest keeping AKH-R specifically in arthropods, together with that of ACP-R, its co-paralog. They also propose to change all the nomenclature of the invertebrate GnRH-like peptides on the basis of the receptor type that they activate. For example, the octopus GnRH, as well as its counterparts in other lophotrochozoans, should be renamed as CRZ because their cognate receptor clearly belongs to the CRZ-R type (344).

Likewise, all AKHs from lophotrochozoans and non-arthropodian ecdysozoans (e.g. nematodes) should be renamed as (true) GnRHs.

As already mentioned, receptors of GnRH-R (GnRH-R1 and GnRH-R2) and CRZ-R (GnRH-R3 and GnRH-R4) types, have been characterized in amphioxus (776). In contrast, only one GnRH-like peptide was found in this group (642), that problably corresponds, for the reasons given above, to CZR. These data clearly suggest the existence of an authentic amphioxus GnRH that remains to be discovered.

All in all, the Zandawala's scenario appears very attractive, since it is based on the hypothesis of co-evolution between peptides and receptors, a process generally observed for neuropeptidergic signaling systems (492). However, further studies are needed to confirm this model, in particular to characterize the ligand-binding properties of the receptors in a larger number of species. For example, such studies would help to clarify the phylogenetic status of the different peptides recently identified in prawn (756), particularly the so-called GnRH, whose place in the Zandawala's nomenclature remains to be determined. The same remark applies regarding the so-called AKH2 and GnRH2 found in the marine annelid Platynereis dumerilii (129).

Phylogenetic analyses show that receptors of the GnRH/CRZ superfamily have close evolutionary relationships with receptors of the vasopressin (VP)/ocytocin (OT) family (492,643). Interestingly, although they are not structurally related, GnRH2, OT and VP genes are tandemly arranged in several vertebral species (252,360,643,790), also suggesting a possible common origin. 4.4.5. GnRH and GnRH-R before bilateria?

The nervous system in cnidarians is well known for its peptide wealth (245). As a matter of fact, a large number of neuropeptides have been isolated from different groups of cnidarians (211). Several reports show that coral tissues contain GnRH-like compounds (18, 812) but they have not been characterized yet. The occurrence of GnRH-like peptides has also been reported in the sea anemone genome [START_REF] Anctil | Chemical transmission in the sea anemone Nematostella vectensis: A genomic perspective[END_REF]. However, recent investigations failed to identify any GnRH-R-like sequence in cnidarian genomes (265,613), suggesting that the GnRH-CRZ signaling system is a bilaterian innovation.

It is noteworthy that an earlier origin of the GnRH system was formerly proposed after the finding that yeast α-mating factor shows some structural and functional similarities to vertebrate GnRHs (435). However, evolutionary relationships between both peptides are unlikely since α-mating factor is known to activate a receptor that does not belong to rhodopsin β-like GPCRs (329).

Functions of GnRH-like peptides: evolutionary perspectives

Reproductive functions of GnRH in chordates

In vertebrates, GnRH1 is the main GnRH form targeted to the pituitary. Its stimulatory effect on gonadotropin release is well established in many species. GnRH1 is thus considered as the major regulator of the hypothalamo-pituitary-gonadal axis whose stimulation leads to gametogenesis and steroid production in the gonads (556,643,921). Consistent with this notion, studies conducted in mice and humans show that GnRH1 null mutations result in hypogonadotropic hypogonadism and infertility [START_REF] Cattanach | Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism[END_REF][START_REF] Chan | GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism[END_REF]. In teleosts species lacking GnRH1, such as zebrafish, GnRH3 is believed to assume the hypophysiotropic role of GnRH1 [START_REF] Abraham | Targeted gonadotropin-releasing hormone-3 neuron ablation in zebrafish: Effects on neurogenesis, neuronal migration, and reproduction[END_REF]744).

The action of GnRH1 is thus closely linked to the presence of a pituitary, which is a vertebrate innovation (643, 740). However, GnRH1 is also produced in and acting on other reproductive tissues. This is particularly the case in the gonads where, in numerous species of fish, amphibians, birds, reptiles and mammals, GnRH1 acts as a paracrine factor involved in the control of both gametogenesis and steroidogenesis (475,477). This is also the case in the placenta (therefore specifically in mammals) where GnRH1 promotes trophoblastic cell invasion and regulates chorionic gonadotropin biosynthesis (670). In addition to its physiological actions, GnRH1 also regulates reproductive behaviors, including female lordosis (656) and male mating behavior (638) in rats.

As mentioned above, GnRH2 is primarily expressed in the vertebrate midbrain and is generally thought to have neuromodulatory actions (337,556). Thus, intracerebroventricular administration of GnRH2 promotes female reproductive behavior in various mammalian species (556). Likewise, GnRH2 stimulates female spawning behavior in goldfish (843).

However, in some teleost and amphibian species, GnRH2 fibers originating from the midbrain were found to project, directly or indirectly, to the pituitary (125,611,921). As a matter of fact, GnRH2, as GnRH1, stimulates gonadotropin synthesis and secretion by pituitary gonadotrope cells (148,489,554).

GnRH3 is implicated in the control of reproductive behavior in teleosts. For instance, in cichlid fish, GnRH3-immunoneutralization decreases nest-building ability of males (542).

Similarly, in medaka, terminal nerve GnRH3 neurons have an essential role for activating mating preferences based on familiarity (559).

In tunicates, GnRH induces the release of gametes, probably via a direct action on the gonads (779), suggesting that GnRH already exerted reproductive functions in the olfactores ancestor (the common ancestor of urochordates plus vertebrates), before the appearance of the pituitary.

Non-reproductive functions of GnRH in chordates

Both, GnRHs, and their receptors are expressed in numerous non-reproductive tissues in the central nervous system (cerebral cortex, hippocampus, cerebellum, …) and in peripheral organs (bladder, adrenal, heart, …) (722), suggesting that GnRH may have a variety of nonreproductive activities. In fact, GnRH1 is released in significant concentrations into the cerebrospinal fluid (CSF) to potentially act outside the hypothalamus [START_REF] Caraty | Gonadotropin-releasing hormone in third ventricular cerebrospinal fluid: Endogenous distribution and exogenous uptake[END_REF]721). GnRH1 can affect pituitary cells other than gonadotropes (722). In particular, GnRH1 stimulates GH release in goldfish (455) and chicken (677). A role of GnRH2 and GnRH3 on early brain regionalization and eye development has also been revealed by knockdown experiments in zebrafish (886). At the behavioral level, GnRH1 is involved in the control of anxiety and depression was reported both in human and rodents (579), while GnRH2 influences feeding behavior (461,777).

Interestingly, a role of GnRH in the control of metamorphosis has been recently observed in tunicates (342), suggesting that, even in the olfactores ancestor, GnRH is not just a reproductive hormone.

Roles of GnRH-like peptides in non-chordates

The first two GnRH-like peptides to be characterized in non-chordates were identified from octopus (313) and C. elegans (424). According to the new Zandawala's nomenclature (see above, 2018), these peptides correspond to CRZ-type and true GnRH-type forms, respectively. At the time of their discovery, both peptides were logically investigated for their reproductive functions. As a matter of fact, the octopus peptide was shown to stimulate oviduct contraction and gonadal steroidogenesis (312, 344), while the nematode peptide was described as a regulator of egg-laying behaviour (424). These findings were thus taken as a strong support to consider both peptides as GnRH homologs (in addition to the fact that they bind to GnRH-like receptors) (423). However, further studies showed that the reproductive functions of GnRH-like peptides are often marginal in non-chordate species.

As mentioned above, AKH-and CRZ-type signalling systems were first characterized in arthropods. Therefore, most of the functional data currently available are from this group, especially from Drosophila (905). In insects, AKH mainly regulates carbohydrate homeostasis, and lipid and carbohydrate mobilization, particularly during flight (216). AKH is also involved in other physiological processes related to locomotion and stress (265), but is generally not linked to reproduction (905). Only a few studies in the cricket (434) and the locust (509) indicate that AKH may have a role in reproduction. In crustaceans, RPCH, the AKH ortholog, modulates gut motility in the lobster (151) and ovarian maturation in the crayfish, in addition to its role in background color adaption initially reproted in the prawn (189). The functions of AKH-like peptides in other taxa are still poorly characterized. AKH has been recently identified in Aplysia (324) and functional assays indicate that it may modulate metabolism, feeding and gut motility, and also affect some gonadal parameters.

Although this peptide is considered as a true GnRH according to the Zandawala's nomenclature (2018) (905). While the functions of ACP, the closest paralog of AKH in arthropods, are still unclear, in a recent study, ACP was shown to play a role in lipid metabolism and inhibition of oocyte proliferation in prawn (756).

As already indicated, CRZ was originally isolated from cockroach on the basis its cardiotropic properties (830). However, such an activity has been so far only documented in a few species. Since then, CRZ has been implicated in a wide range of functions in insects, including the initiation of ecdysis behaviors in the moth (362), induction of cuticular pigmentation in the locust (771), reduction of the spinning rate and pupal development in the silkworm (767), testicular development and spermatogenesis in the prawn (711). In ants, CRZ controls social behavior and caste identity (236). As for GnRH, the functions of CRZ in other taxa are still poorly known. The reproductive functions of CRZ in octopus have been mentioned above, but octopus CRZ (according to the Zandawala's nomenclature) has also non-reproductive functions, in particular on the heart and muscles (312,344). In Aplysia, CRZ affects many processes including motor function, feeding and neuronal activities but has no significant effect on reproduction (753, 802).

Overall, GnRH-type and CRZ-type peptides are pleiotropic hormones that have both overlapping and specific properties, but do not exhibit clear patterns of functions emerges, thus making difficult to infer their ancestral functions in Urbilateria, the last common ancestor of bilaterians. The only (quasi) certainty is that the critical role of GnRH as a reproductive activator is a characteristic unique to vertebrates (654), likely related to the innovation of the pituitary gland in this group.

Origin and evolution of brain RF-amide peptides in the limelight for reproduction

Two types of brain peptides, namely kisspeptin and GnIH/RFRP, have been subjected to most attention in the field of reproductive physiology since the early 2000s. Both belong to the superfamily of RF-amide peptides and have been proposed as new major actors in the neuroendocrine control of reproduction in vertebrates.

History and evolutionary relationships of the RF-amide peptides

Discovery of RF-amide peptides in mollusks

In 1972, a substance, designated peak C, was isolated in all major classes of the phylum Mollusca for its cardioexcitatory activity [START_REF] Agarwal | The distribution of cardioactive agents among Molluscan species and tissues[END_REF]. Five years later, peak C was purified from cerebral ganglion extracts of the sunray venus clam, Macrocallista nimbosa (623). The neuropeptide identified, FMRFamide, was named after the letter abbreviations of its four amino acids, phenylalanine, methionine, arginine and phenylalanine, and its amidated Cterminal sequence (623). Since then, FMRFamide along with its structurally related neuropeptides named FMRFamide-related peptides (FaRPs) or FMRFamide-like peptides (FLPs) remains the best-investigated family of neuropeptides in mollusks.

RF-amide peptides superfamily in vertebrates

The first vertebrate member of the RF-amide family (peptides ending with Arg-Phe-NH 2 ) was isolated and sequenced (Leu-Pro-Leu-Arg-Phe-NH 2 : LPLRFamide) from chicken brain in 1983 (152). This peptide was subsequently recognized as a fragment of a longer RF-amide peptide, gonadotropin-inhibitory hormone (GnIH) (for review: (806). Since 1983, a number of neuropeptides sharing the typical C-terminal RF-amide (RFa) signature were discovered in all major animal phyla (174,318,904). [START_REF] Dockray | A novel active pentapeptide from chicken brain identified by antibodies to FMRFamide[END_REF] suggested designating the mammalian RF-amide genes, farp-1 to farp-5 in the chronological order they were described ( 153 (104,213,322). These five distinct genes thus encode seven peptides in mammals (153,630). The farp nomenclature based on chronology of discovery has not been followed by other authors (630). However, a similar classification into five groups has been adopted (for review: (826)) and further validated by phylogenetical analyses performed on sequences from various vertebrates including mammals, other tetrapods, teleosts and lamprey (570).

These groups of RF-amide peptides were named by the authors: PQRFa (NPFF) group corresponding to farp-1; PrRP group corresponding to farp-2; LPXRFa (GnIH) group corresponding to farp-3; metastin (kisspeptin) group corresponding to farp-4; and QRFP (26RFa) group corresponding to farp-5 (for review: (805)).

All the RF-amide peptides bind to G protein-coupled receptors (GPCRs). Dockray suggested, as for farps, to designate the receptors to the RF-amide peptides in the order they were identified as putative RFamide receptors: accordingly, rfr-1 for PrRP (farp-2) receptor (280); rfrp-2 for RFRP-1 and RFRP-3/NPVF/GnIH (farp-3); rfr-3 for NPFF and NPAF (farp-1) receptors [START_REF] Bonini | Identification and characterization of two G protein-coupled receptors for neuropeptide FF[END_REF]176,281); rfr-4 for metastin/kisspeptin (farp-4) receptor (375, 513, 549); rfr-5 for QRFP/26RF (farp-5) receptor (213,322). Using phylogenetical analyses of more than 800 human GPCR sequences, [START_REF] Fredriksson | The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints[END_REF] showed five main families of GPCRs in human, which they named glutamate, rhodopsin, adhesion, frizzled/taste2 and secretin (208). The rhodopsin family was divided into four groups: α, β, γ and δ (208). Kisspeptin receptor (also named GPR54 or rfr-4) belongs to the γ group, more specifically to the SOG receptor cluster, together with the receptors for non-RFamide peptides, somatostatin (S), opioid (O) and galanin (G) (208). Receptors of NPFF (rfr-3), GnIH/RFRP (rfr-2), PrRP (rfr-1) and QRFP (rfr-5) cluster within the β group, with receptors for non-RFamide peptides, neuropeptide Y (NPY), cholecystokinin, GnRH, tachykinin, ghrelin, and neuromedin U (208).

Several studies, based on synteny analysis and phylogenetic relationships of RF-amide peptides and receptors, provide new insights into the RF-amide peptide superfamily (for review: (904)). A gene encoding a PQRFa peptide has been identified in a cephalochordate, the amphioxus, indicating the presence of a pqrf gene at least in a chordate ancestor (565). This ancestral gene likely gave rise to gnih (farp-3) and its sister gene npff (farp-1), via one of the two rounds of whole genome duplications (1R/ 2R) that occurred early in the vertebrate lineage ((565); for reviews: (807, 904)). The authors also reported phylogenetical relationships between NPFF, GnIH and QRFP (farp-5), suggesting a close evolutionary relationship between these three groups of RF-amide peptides (904). Kisspeptin (farp-4) has been proposed to be evolutionary more related to non RF-amide peptides, galanin and spexin, than to other RF-amide peptides, and proposed to be classified as a member of the galanin/spexin family ((359); for review: (904)). PrRP receptors likely share a common ancestry with NPY receptors as reported by Lagerström and collaborators (385), linking the PrRP group (farp-2) more to a non-RF-amide peptide family than to the other RF-amide peptide groups. The grouping of the various RF-amide peptide subfamilies/groups in a same RF-amide superfamily is thus currently a matter of debate (Figure 9).

GnIH (farp-3

) and evolutionary-related peptides (NPFF and QRFP) (farp-1 and -5)

Discovery of GnIH in birds: direct inhibitory role on pituitary gonadotropins

In 2000, Tsutsui and collaborators reported the isolation and characterization, from quail brain, of a novel neuropeptide, having an RFa motif at the C-terminus, which dosedependently inhibits the gonadotropin, luteinizing-hormone (LH), release in vitro from quail anterior pituitaries. They named this peptide gonadotropin-inhibitory hormone (GnIH) (808).

In the quail, starling and duck, the GnIH precursor mRNA encodes a polypeptide that can potentially be cleaved into three mature peptides with a C-terminal LPXRF-amide sequence (X=L or Q), named GnIH-related peptide-1 (GnIH-RP1), GnIH and GnIH-RP2 (quail: (671); starling: (814); duck: (207); for review: (378)). GnIH was identified as a mature endogenous peptide by mass spectrometry analyses, in the brain of quail (808), starling Sturnus vulgaris (814), zebra finch Taeniopygia guttata (788) and chicken (472), while GnIH-RP2 was also indentified in the brain of quail (671).

In 2005, Tsutsui and colleagues identified a GnIH receptor (898), using primers designed from the sequence of GPR147, a novel GPCR, also called NPFF receptor 1 (NPFFR-1) since its discovery together with another NPFF receptor (NPFFR-2 or GPR74) in mammals [START_REF] Bonini | Identification and characterization of two G protein-coupled receptors for neuropeptide FF[END_REF].

As GnIH has higher affinity for NPFFR-1, the latter is considered to be the primary receptor for GnIH [START_REF] Bonini | Identification and characterization of two G protein-coupled receptors for neuropeptide FF[END_REF]426).

The direct inhibitory action of quail GnIH on LH release was confirmed in another bird, the chicken. An inhibitory effect of GnIH on LH release by pituitary slices was reported in the sexually immature female White Leghorn while it was not observed in vitro in sexually mature birds and nor on FSH release at both stages (446). In a hybrid of White Leghorn and Silkie Breed, GnIH inhibits LH release (but not mRNA expression), as well as FSH release and mRNA in pituitary explants (117).

The direct effect of GnIH at the pituitary level is also supported by the detection of gnihr mRNA in the pituitary of various bird species (quail: (898); starling and quail: [START_REF] Bentley | Gonadotropin-inhibitory hormone and its receptor in the avian reproductive system[END_REF]) and by the colocalization of GnIH receptor immunoreactivity with LHβ or FSHβ mRNA expression in the chicken pituitary gland (446).

GnIH inhibitory role at the brain and gonadal levels in birds

GnIH may also directly influence GnRH secretion as GnIH-ir fibers are observed in contact with GnRH-ir neurons in many bird species (sparrow: [START_REF] Bentley | Gonadotropin-inhibitory peptide in song sparrows (Melospiza melodia) in different reproductive conditions, and in house sparrows (Passer domesticus) relative to chicken-gonadotropin-releasing hormone[END_REF]; for review: ( 49 Injection of GnIH rapidly reduces plasma LH and attenuates GnRH-induced rise in plasma LH in sparrow [START_REF] Bentley | Rapid inhibition of female sexual behavior by gonadotropin-inhibitory hormone (GnIH)[END_REF]569). In quail, continuous administration of GnIH for 2 weeks decreases LHβ mRNA levels (818). In the Pekin duck, icv injection of GnIH reduces plasma LH concentrations, while administration of GnIH-RP1 has no effect (207). One study reported no effect of GnIH on LH plasma levels in a bird species: in the Rufous-winged sparrow, GnIH does not affect basal or GnRH-stimulated plasma LH levels (149).

PCR analyses reveal the presence of GnIH as well as GnIH-R mRNAs in the testis, ovary and accessory reproductive organs (oviduct, epididymis and vas deferens) in starling and quail [START_REF] Bentley | Gonadotropin-inhibitory hormone and its receptor in the avian reproductive system[END_REF]. Similarly, transcripts for GnIH and GnIH-R are detected in the testis of house sparrow Passer domesticus ((476); for review: (475)). In this latter species, GnIH decreases testosterone secretion from cultured testis (476). This indicates possible local, autocrine/paracrine actions of GnIH in the gonads in birds.

GnIH in mammals

The discovery of GnIH in birds has prompted investigations in mammals. The GnIH precursor cDNAs identified from mammalian brain encode two GnIH peptides, also known as RFamide-related peptides (RFRP): RFRP-1 and -3 (for reviews, see (804-806); rat: (281, 822); mouse : (281); Siberian hamster (813); bovine (212,281,900); monkey (815); human (281, 816)). Like avian GnIH and GnIH-RPs, all these peptides possess a common C-terminal LPXRFamide (X=L or Q) motif, with RFRP-1 being a C-terminal LPLRFamide peptide and RFRP-3 a LPQRFamide peptide (for review: (807)). In human and bovine (not in rat and mouse), a third peptide, RFRP-2, is also predicted, but is a LPLRSamide peptide or a LPLRLamide peptide, respectively (281). This RFRP-2 peptide could not be detected in an extract of human hypothalamus by using an avian GnIH antibody-conjugated immunoaffinity column and mass spectrometry, possibly due to its different C-terminal motif or because it is not processed from the precursor (816). The rat GPR147 does not respond to hRFRP-2, showing the importance of the C-terminal RFamide for the binding to the receptor (281, 816).

The RFRP-2 sequence is absent from the RFRP precursor in the Siberian hamster (813). Li and collaborators suggested that the pig GnIH precursor encodes three RFRP peptides, two with an LPLRFamide C-terminal sequence and one with an LPQRFamide C-terminal motif (416). The authors reported also similar characteristics in the rabbit and golden hamster GnIH precursors (416).

In all mammalian species, as in birds, RFRP fiber terminals form close appositions with GnRH neurons (hamsters (377); rats (325, 377); mice (377, 885); sheep (726); monkeys (815); humans (816)). In the mouse, direct application of RFRP-3 on cultured brain slices decreases the firing rate of a subpopulation of GnRH neurons, and this effect is maintained when amino acid transmission is blocked, suggesting a direct suppressive action of RFRP-3 on the excitability of GnRH neurons (165).

In addition to its effects on GnRH neurons, GnIH may also act directly at the pituitary level via its release in the portal blood in mammals as in birds. GPR147 (also referred to as NPFFR-1), is expressed in the pituitary in rat (281), Syrian hamster (230) and human (816), and RFRP-ir fibers are observed in the external layer of the ME in hamsters (230), sheep (118) and humans (815,816). However, other studies using a different antiserum failed to detect RFRP-ir in the ME of rat brain and ip injection of the retrograde tracer Fluorogold did not label RFRP cell bodies (639). RFRP-3 inhibits GnRH-stimulated gonadotropin synthesis in pituitary gonadotropes in sheep in vitro (664), supporting a potential action at the pituitary level. In Artiodactylae, RFRP-3 inhibits GnRH-induced, but not basal, LH and FSH secretion and expression by primary cultures of pituitary cells (ewe: (118, 664); bovine: (332); pig:

(415)). In rat, [START_REF] Pineda | Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies[END_REF] observed an inhibitory effect of RFRP-3 on both basal and GnRH-stimulated LH secretion (610), while other studies reported no effect [START_REF] Anderson | Central and peripheral effects of RFamide-related peptide-3 on luteinizing hormone and prolactin secretion in rats[END_REF] or an effect only on GnRH-stimulated LH release (517). In the Syrian hamster, [START_REF] Ancel | Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male Syrian hamster: Downloaded from www[END_REF] found no effect on either basal or stimulated LH release [START_REF] Ancel | Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male Syrian hamster: Downloaded from www[END_REF].

The presence of GnIH and its receptor in the mammalian gonads (Syrian hamster testis (914); human ovary (550); pig ovary and testis (416, 916)) suggests, like in birds, possible autocrine/paracrine regulations via a local gonadal GnIH system. Indeed, in the mouse, in vivo and in vitro studies show that GnIH/RFRP-3 treatment inhibits follicular development and ovarian steroidogenesis in the female (719), as well as testicular steroidogenesis and spermatogenesis in the male [START_REF] Anjum | Inhibitory roles of the mammalian GnIH ortholog RFRP3 in testicular activities in adult mice[END_REF]. Similarly, GnIH/RFRP-3 inhibits the synthesis and release of estradiol by ovarian granulosa cells (415) and of testosterone by Leydig cells (916) in vitro in pigs. Interestingly, a recent study investigating the role of RFRP-1 on ovarian activities reported a stimulatory effect of RFRP-1 on ovarian steroidogenesis at proestrus in the mouse, but an inhibitory action on ovarian folliculogenesis (141).

Using a mouse line with genetic inactivation of NPFFR-1, it has been demonstrated that the NPFFR-1 pathway is dispensable for preserved puberty and fertility ((401); for review: (402)). To the best of our knowledge, there is no report on the possible impact of gnih (npvf) gene inactivation in mice. In the bullfrog Rana catesbeiana, a RF-amide peptide, isolated from hypothalami, showed high (75%) sequence identity with quail GnIH (372). It was designated fGRP for "frog GHreleasing peptide" as it exhibits growth hormone-releasing activity (372). In parallel, the same peptide was isolated from the brain of the European green frog Rana esculenta, and named R-RFa for "Rana-RFamide" (104). The cloning of a cDNA for fGRP revealed that the deduced precursor encodes one fGRP and three putative fGRP-related peptides (fGRP-RP1, -RP2 and -RP3) (672), These four peptides were all identified as mature peptides and found to have a common C-terminal LPXRFamide with avian and mammalian GnIHs (824). Two of these peptides (fGRP and fGRP-RP2) stimulate GH and/or PRL release in vivo and in vitro, while the other two (fGRP-RP1 and fGRP-RP3) have no effects ((372, 824); for review: (823)).

None of them is able to modify the release of gonadotropins (372,824). The localization in the amphibian brain is in agreement with other vertebrate distribution as positive neurons (cell bodies) are present in the periventricular region of the hypothalamus (372,612,673). In contrast, nerve fibers are widely distributed throughout the brain (612) notably in the olfactory system ((194, 612). An urodele, the Japanese red-bellied newt Cynops pyrrhogaster possesses four GnIH peptides (nLPXRFa-1, nLPXRFa-2, nLPXRFa-3 and nLPXRFa-4) but no functional studies have been performed yet (114). The GnIH sytem and its functional significance in amphibians has been recently reviewed (315).

c-In basal sarcopterygian and actinopterygian

In a basal sarcopterygian, the coelacanth Latimeria chalumnae, a GnIH precursor gene has been identified, encoding three putative LPXRFamide peptides and one LPXRFamide-like peptide, which align with human RFRP-1/quail GnIH-RP1, human RFRP-2/quail GnIH, human RFRP-3, and quail GnIH-RP2, respectively (for review: (516)).

In a basal, non-teleost actinopterygian, the spotted gar Lepisosteus oculatus, a GnIH precursor encodes three putative LPXRFamide peptides, which align with human RFRP-1/quail GnIH-RP1, human RFRP-2/quail GnIH, and human RFRP-3, respectively (for review: (516)).

d -In teleosts: positive and negative effects on gonadotropins

Up to now, in teleosts, only a single gene for GnIH has been identified as in the spotted gar.

However, owing to the teleost specific WGD (3R), two GnIH genes would have been expected. This suggests the loss of one of the 3R-GnIH duplicated paralogs shortly after the 3R event.

Most of the teleost GnIH precursors encode three LPXRFamide or LPXRFamide-like peptides which align with human RFRP-1/quail GnIH-RP1, human RFRP-2/quail GnIH, and human RFRP-3, respectively (for reviews: (516, 807)). In some species, the precursor encodes only two peptides which align with human RFRP-1/quail GnIH-RP1, and human RFRP-2/quail GnIH, respectively. Most GnIHs identified in teleosts possess the common Cterminal LPXRFamide motif observed in other vertebrate GnIHs.

Concerning the physiological role of GnIH in the control of the gonadotropic axis, the situation appears more complex in teleosts than in other vertebrates. In the goldfish, GnIH inhibits GnRH-stimulated lhβ and fshβ expression by primary cultures of pituitary cells, with no effect on basal gonadotropin expression (625), while other studies describe either stimulatory, inhibitory or no effect on both basal and stimulated LH (release and expression), depending on the gonadal stage (510, 511). A stimulatory effect of goldfish LPXRa was observed on LH and FSH release by salmon pituitary cells [START_REF] Amano | Novel fish hypothalamic neuropeptides stimulate the release of gonadotrophins and growth hormone from the pituitary of sockeye salmon[END_REF]. Similarly, goldfish LPXRa stimulates lh and fsh expression by whole pituitaries of grass puffer (700). In tilapia, treatment of pituitary cells in primary culture with tilapia LPXRFa-2 induces a significant increase in both FSH and LH release [START_REF] Biran | LPXRFa, the piscine ortholog of GnIH, and LPXRF receptor positively regulate gonadotropin Downloaded from www.physiology.org/journal/physrev[END_REF]. In Cichlasoma dimerus, homologous LPQRFa-1 decreases LH and FSH release, while LPQRFa-2 is able to stimulate FSH release (whole pituitaries: (899)). In a basal teleost, the eel Anguilla anguilla, ongoing studies indicate that the three peptides encoded by the eel gnih gene exert an inhibitory effect on lhβ mRNA expression by eel pituitary cells.

e-In cyclostomes (agnathans)

Tsutsui and colleagues in collaboration with Sower's laboratory (563) have cloned the lamprey GnIH precursor cDNA that encodes a precursor encompassing three GnIH peptides (lamprey LPXRFa-1a, LPXRFa-1b and lamprey LPXRFa-2). The lamprey GnIH peptides have a C-terminal PQRFamide motif, unlike most GnIHs, but like NPFF, in gnathostomes. In vivo administration of one of the lamprey GnIHs (lamprey LPXRFa-2) stimulates the expression of lamprey GnRH (GnRH3) in the hypothalamus and gonadotropin β mRNA in the pituitary (563). Thus, the authors suggest that GnIH may have emerged in agnathans as a stimulatory neuropeptide that subsequently diverged to an inhibitory neuropeptide during the course of evolution from basal vertebrates to later-evolved vertebrates, such as birds and mammals (563). 5.2.5. Origin and evolution of GnIH and its receptors in vertebrates Osugi and collaborators showed that agnathans possess both GnIH and NPFF genes, with the common C-terminal PQRFamide motif (563, 570).

Tsutsui and colleagues hypothesized that vertebrate GnIH and NPFF genes may derive from a common ancestral gene present in protochordates (for review: (807)). In protochordates, a precursor cDNA of amphioxus PQRFamide peptides was then identified. This precursor encodes three mature peptides characterized by immunoaffinity purification and mass spectrometry (565). The conserved syntenic region around the loci of the amphioxus PQRFamide peptide gene, as well as of the GnIH gene and NPFF gene in vertebrates (565), suggests that GnIH and NPFF paralogous genes may originate from WGD in early vertebrates (for review: (567)) (Figure 9). As amphioxus PQRFamide peptides inhibit forskolin-induced CRE-luciferase activity in COS-7 cells expressing the amphioxus PQRFa receptor 1 (565), the authors suggested that the common ancestral peptide of GnIH and NPFF has played an inhibitory role in reproduction in ancestral chordates (807). The inhibitory role of the ancestral peptide would have been conserved for GnIHs in mammals, birds and some teleosts, whereas a change from inhibitory to stimulatory role would have occurred in agnathans and some teleosts (807). In fact, the GH-and PRL-releasing activity of GnIH in amphibians with the lack of effect on gonadotropin secretion suggests a larger flexibility in the possible physiological roles of GnIH peptides in the course of vertebrate evolution.

Concerning GnIH receptors, two GPCRs have been identified in birds and mammals:

(LPXRF-R or NPFFR-1 or GnIHR or OT7T022) considered as the primary GnIH receptor and GPR74 (PQRF-R or NPFFR-2) with a lower affinity for GnIH (for review: (543)).

In teleosts, up to three different GnIH receptor genes (gnihr1, gnihr2 and gnihr3), that share high sequence identity with the mammalian and avian GPR147, have been isolated in zebrafish (913), goldfish (625) and common carp (599). This may reflect the impact of teleost specific WGD (3R) or of the additional WGD that occurred in some cyprinids (4R in goldfish and some carps). However, in most teleosts, only one receptor has been identified so far (grass puffer LPXRF-R (700); tilapia LPXRF-R ( 60); orange-spotted grouper GnIHR (858); clownfish GnIHR (113); tongue sole LPXRFa-R ( 853)). Further investigations are thus clearly needed.

Elphick and Mirabeau have identified a GnIH/NPFF-type receptor gene in the genome database of the hemichordate Saccoglossus kowalevski (174). Phylogenetic analyses grouped the receptors of vertebrates into NPFFR-1 (GPR147) and NPFFR-2 (GPR74), and the receptors of insects into SIFR (817). Deuterostomian NPFFR genes have already been proposed to share a common evolutionary origin with protostomian SIFR genes (492).

NPFF (PQRF) group (farp-1)

The first NPFF (PQRF) peptide to be reported was isolated from the bovine brain and characterized as a pain modulatory peptide (896). NPFF peptides possess a similar C-terminal structure (PQRFamide motif) as some GnIH peptides (for review: (577)). As previously discussed, npff and gnih genes are paralogous genes that likely emerged from WGD in early vertebrates. As GnIH precursors, the PQRFa precursor encompasses two to three putative mature peptides: NPFF and NPAF in mammals, NPFF and NPAF in teleosts, and PQRFa, PQRFa-RP1 and PQRFa-RP-2 in agnathans (lamprey and hagfish) (for review: (577)).

NPFF peptides have been largely investigated for their role in the control of nociception (for review: [START_REF] Ayachi | Involvement of mammalian RF-amide peptides and their receptors in the modulation of nociception in rodents[END_REF]). Other actions have been also reported such as increasing arterial blood pressure and water intake, while decreasing food intake in mammals (for review: (577)). Compared to GnIH or kisspeptin, few studies have been carried out to investigate the possible role of NPFF in reproduction. In teleosts, one study reported that bath application of medaka NPFF inhibits the pacemaker activity of terminal nerve GnRH neurons in the dwarf gourami (653). In agnathans, one of the hagfish NPFF peptides directly stimulates pituitary expression of gonadotropin β mRNA (568), while the lamprey peptides appear to possess a stimulatory effect only on GnRH2 secretion (140). These data suggest that PQRFamide peptides may play a role in the reproductive system of lower vertebrates and that they might have adopted new functions during the course of vertebrate evolution (568).

QRFP (26RFa) group (farp-5)

In 2003, a new peptide family was simultaneously identified by three different laboratories (104,213,322). The first research group isolated the peptide from a frog brain extract, and named it 26RFa after its 26 amino acid sequence and RF terminal motif (104). The other two research groups identified the peptide while searching for ligands to an orphan GPCR (GPR103 also referred to as AQ27 or SP9155) (213, 322). Fukusumi and collaborators named it QRFP, after its pyroglutamylated arginine-phenylalanine-amide signature; the peptide consists of 43 amino acid residues (213). Jiang and collaborators (2003) named it P52 and its precursor protein, P518 (322). Comparative studies indicated that amphibian 26RFa and mammalian QRFP/P52 are orthologs (825). Phylogeny analyses of RF-amide peptides and receptors suggested a close relationship between QRFP (26RFa) (farp-5) on the one hand and the GnIH and NPFF groups (farp-3 and farp-1) on the other hand, likely resulting from local gene duplication, preceding vertebrate WGD (904) (Figure 9).

A QRFP (26RFa) gene has been described in amphioxus (492, 889), suggesting that the gene existed in chordates before the emergence of vertebrates. As all vertebrates studied so far possess a single gene, this suggests that duplicated paralogs resulting from the successive 1R, 2R WGD in early vertebrates and from 3R WGD in early teleosts, might have been lost (for review: (404)).

The main role reported for 26RFa/QRFP is the control of feeding behaviour with a potent orexigenic effect in mammals and birds, while it may also exert other various functions (for reviews: (102,103,105,404,825)). Concerning reproductive functions, in vitro and in vivo studies support the involvement of 26RFa in the control of the gonadotropic axis in mammals (528). 26RFa dose-dependently stimulates basal and GnRH-induced LH secretion by male and cyclic female rat pituitaries in vitro (528). Similarly, in vivo (icv or systemic) injection of 26RFa induces a significant increase of serum LH levels in cyclic and ovariectomized females (528). Patel and collaborators tested the more potent GPR103 ligand, QRFP43, in vivo and in vitro (594). They reported that icv injection of QRFP43 to male rats increases plasma LH and FSH levels; in contrast, intraperitoneal administration does not influence circulating gonadotropin levels (594). In vitro, QRFP43 stimulates GnRH release from hypothalamic explants from male rats and from the immortalized hypothalamic GnRH-producing neurons (GT1-7 cells) (594). In teleosts, one study in the goldfish reported that intraperitoneal injection of 26RFa increases plasma LH levels; the peptide may exert its action at the brain level, since 26RFa has no direct effect on LH release in vitro by primary cultures of pituitary cells (431).

A raising star in mammalian reproduction: Kisspeptin (farp-4)

Discovery of Kiss in mammals

In 1996, a metastasis suppressor gene for melanoma cells was identified and called Kiss-1… as a tribute to the chocolate speciality of the city of the authors (227). Then, in 1999, the cDNA of a novel GPCR was isolated from rat brain and named GPR54 (396). Since the highest identity of this orphan GPCR was observed with the galanin receptors and since its cerebral distribution was similar to those of galanin receptors, the authors suggested that the endogenous ligand of GPR54 may have a peptidergic nature (396). Two years later, the natural ligands of GPR54 were isolated from human placenta (375). The Kiss-1 gene encodes a 54 amino-acid peptide which may be further processed into shorter peptides of 14 and 13 amino-acids (290, 549), all designated as kisspeptins (375). The peptide of 54 amino-acid residues was also named metastin (549). The 10-amino acid C-terminal fragment of kisspeptins (or kiss peptides) carries the biological activity (375). The functional importance of the C-terminal amidation was shown by the lack of binding and functional response for non-amidated synthetic kisspeptins (375).

A few years later, a pivotal role of kisspeptin in the control of reproduction was revealed. The discovery by three research groups (214, 648, 693) that inactivation of kisspeptin receptor (GPR54) leads to hypogonadotropic hypogonadism in human patients (loss-of-function mutations) and in mice (knock-out, KO) retained attention of reproductive endocrinologists and initiated intensive research on kisspeptin for many years. Hypogonadotropic hypogonadism was also observed in Kiss1 KO mice (135). Conversely, mutations leading to higher resistance of kisspeptin to degradation (714) or prolonged activation of GPR54 (774) can induce precocious puberty onset in humans (for review: (714)). neurons. In addition, coexpression of GPR54 mRNA by GnRH neurons is observed in rat (307) and mouse (483). Icv administration of kisspeptin in sheep also induces a robust release of GnRH into the cerebrospinal fluid (483). Intraperitoneal (ip) injection of kisspeptin in wild-type mice stimulates LH and FSH release, but has no effect in gpr54-/-mice (483). All these data define the kisspeptin system (ligand and receptor) as a major stimulator of the gonadotropic axis via induction of GnRH in mammals (rodents, sheep and primates). In rats and mice, two distinct subpopulations of kisspeptin neurons with different roles on GnRH/gonadotropic axis have been identified: the hypothalamic arcuate nucleus subpopulation is involved in the pulse mode of GnRH/LH release while the anteroventral periventricular nucleus subopulation is implicated in the surge mode of GnRH/LH release (for review: (820). A direct action of kisspeptin on GnRH neurons was demonstrated in vitro, as kisspeptin induces GnRH release from mediobasal hypothalamus (MBH) explants, while this did not occur in MBH explants from Gpr54 null mice (770). Primary cultures of whole fetal rat brain respond to exogenous kisspeptin with increased gnrh mRNA expression (750).

Role of

Using mouse GnRH-secreting neuronal cell lines (GT1-7 cells: (480); GN11 cells: (631)), two studies also showed a stimulatory effect of kisspeptin on GnRH secretion and mRNA levels (GT1-7 and GN11 cells: (540); GT1-7 cells: (780)); in contrast, another study using GT1-7 cells showed that kisspeptin fails to stimulate GnRH expression while increasing GnRH receptor transcriptional activity ((751); for review: (343)).

b-Direct action on pituitary and gonads

The expression of GPR54 in the pituitary gland and in particular on LHβ cells in rat, ovine and human suggests a potential direct action on pituitary cells (for reviews: (218, 636)). In most mammals, kisspeptin-10 is able to stimulate LH secretion in vitro (rat: (527); bovine and porcine: (759); ovine: (727); baboon: (440)). However, other studies in rats have been unable to find any detectable action of kisspeptin on LH directly at the pituitary level (464,783).

Few data are available on in vitro FSH regulation by kisspeptin in mammals. Either no effect on FSH release (baboon: (440)) or moderate stimulation of GnRH-enhanced FSH secretion (526) has been reported. Concerning the transcriptional regulation of gonadotropins, Witham and collaborators showed, using both the mouse pituitary gonadotrope cell line LβT2 and murine primary pituitary cells, that kisspeptin induces LHβ and FSHβ expression through the activation of KissR-1 signaling via PKC (876).

Expression of kisspeptin, as well as GPR54, in mammalian ovary (rat: [START_REF] Castellano | Expression of KiSS-1 in rat ovary: Putative local regulator of ovulation?[END_REF]; swine: [START_REF] Basini | Presence and function of kisspeptin/KISS1R system in swine ovarian follicles[END_REF]) and testis (mice: (854); goat: (660); primate: (306)) supports a role of the local kisspeptin system at the gonadal level. In vitro studies on the functional role of the kisspeptin system in gonads have so far given contradictory results in mammals, with no (mouse Leydig cells: (479, 854); Rhesus monkey testes: ( 769)) or stimulatory effect on steroidogenesis (swine granulosa cells: [START_REF] Basini | Presence and function of kisspeptin/KISS1R system in swine ovarian follicles[END_REF]; goat Leydig cells: (661)). In addition, kisspeptin was shown to stimulate fertilization capacity of mouse spermatozoa (292). 5.3.3. Multiple Kiss and Kiss receptor genes in vertebrates: impact of WGD a-1R and 2R WGD origin of multiple Kiss genes followed by gene losses during vertebrate evolution (Figure 10) While, in rodents, a single gene (Kiss1) is present, up to three Kiss genes have been identified in other vertebrate lineages including cyclostomes (2 genes), chondrichthyes (2 or 3 genes), actinopterygians (1 or 2 genes), basal sarcopterygian (coelacanth: 3 genes), amphibians (up to 3 genes), sauropsids (0, 1 or 2 genes), as well as in non-rodents mammals (1 or 2 genes). Phylogenic analysis classified the identified Kiss genes into three different clades (i.e., Kiss1, Kiss2 and Kiss3 clades, leading to a phylogenetically-based nomenclature according to Pasquier and collaborators (587,592). The current three Kiss genes may derive from a single ancestral gene duplicated through the two successive WGD (1R and 2R) in early vertebrates (for review: (587)). These 1R and 2R events should have yielded four different Kiss genes in vertebrates, and syntenic analysis supports the potential existence of a fourth Kiss gene (Kiss4) in early vertebrates (587, 592).

The current diversity of Kiss gene numbers (from 0 to 3) in extant vertebrate species is the result of multiple and independent pseudogenization processes and gene loss events during vertebrate evolution that occurred after the 1R and 2R events (for review: (587)). The loss of the putative Kiss4 gene would have occurred early in vertebrate evolution (shortly after the 2R) as it is absent in all extant species of key phylogenetical positions. Additional Kiss gene loss events would have happened, as only a few extant representative species of chondrichthyans (elephant shark) and sarcopterygians (coelacanth and Xenopus) possess three Kiss genes. Kiss3 would have been lost independently in early actinopterygians and early amniotes, while Kiss1 would have been lost independently in some teleosts and sauropsids, and Kiss2 in some sauropsids and some mammals. The Kiss1 and Kiss2 genes are thus the most frequent Kiss genes in extant vertebrates. Among sauropsids, both Kiss1 and Kiss2 genes are present in some groups such as chelonians (turtle) and crocodilians, while Kiss1 has apparently been lost independently in some squamates (anoles) and in birds. Furthermore, Kiss2 has undergone pseudogenisation and loss during bird evolution, leading to the lack of Kiss in some species such as the chicken, falcon or parrot (591). In mammals, Kiss1 and Kiss2 are both present in a prototherian mammal (platypus), while Kiss2 has undergone pseudogenisation and loss in metatherian (opossum) and eutherian mammals (for review:

(587)). Although a Kiss2-like gene is present in the genomes of primates including humans, due to the lack of amidation signal in the precursor, the endogenous Kiss2 peptide may not be functional or produced (564).

While teleost 3R WGD (TWGD) should have generated additional Kiss paralogs, extant teleost species do not possess more Kiss genes than a non-teleost actinopterygian (spotted gar) (Kiss1 and Kiss2) (592). The lack of impact of TWGD suggests a massive loss of 3R-Kiss paralogs shortly after the 3R event. Furthermore, additional loss of Kiss1 led to the presence of a single Kiss gene (Kiss2) in some teleosts such as the tetraodon and stickleback (587). b-1R and 2R WGD origin of multiple Kiss receptor genes followed by gene losses during vertebrate evolution (Figure 11) While, in mammals, only a single gene encodes kisspeptin receptor (KissR), several KissR genes have been identified in other vertebrates including chondrichthyes (2 genes), teleosts (1, 2 or 3 genes), amphibians (3 genes) and sauropsids (0, 1 or 2 genes) (for review: (587)). As for Kiss genes, the multiple KissR genes may arose from 1R and 2R, so that the potential existence of four KissR paralogs in vertebrates has been hypothetized (361,398). Actually, a fourth KissR has been discovered in extant representative species of basal sarcopterygians (coelacanth) and actinopterygians (spotted gar). Phylogenetic analysis classified the identified Kiss genes into four different clades (i.e., KissR1, KissR2, KissR3 and KissR4 clades), according to the nomenclature by Pasquier and colleagues (587,589). Phylogenetic and syntenic analyses indicate that these four paralogs likely resulted from 1R and 2R WGD ((589, 592). This suggests that a KissR ancestral gene was present before the emergence of vertebrates. In agreement with this hypothesis, KissR homologous genes have been identified in non-vertebrate deuterostomes (174). The KissR1 and KissR3 clades are more closely related to each other than to KissR2, and likely represent sister clades stemming from 2R (587). A phylogenetic reconstruction of a gene family associated with the KissR paralogon, the PALM family (298), also supports the hypothesis that 2R gave rise to KissR1 and KissR3 sister paralogons on the one hand, and of KissR2 and KissR4 sister paralogons on the other hand.

As for the Kiss genes, after the 1R and 2R events, the history of the KissR family was driven, throughout vertebrate evolution, by multiple gene loss events leading to the current diversity of KissR. KissR4 has been lost independently in the actinopterygian and sarcopterygian lineages. In actinopterygians, this event has likely occurred in a teleost ancestor after the emergence of holosteans (e.g. the spotted gar still possesses the four KissRs). Among sarcopterygians, KissR4, which is still present in a basal species (coelacanth) in some sauropsids (chelonian and squamates) and in prototherian mammals (platypus), has been lost independently in the amphibian lineage, in some sauropsids (crocodilians) and in the common ancestor of metatherian and eutherian mammals, including human which possesses a single KissR (KissR1).

As for Kiss, due to massive gene losses, no effect of the teleost-specific TGWD can be recorded on the current number of KissR in teleosts (587,589,592). This is further supported by a recent study in pejerrey Odonthesthes bonariensis including phylogenetic analyses (791). c-Gene conservation or losses and variations in Kiss/KissR couples Comparison of the evolutionary histories of Kiss and KissR families (Figures 10 and11) highlights both common features and divergences (587). Four Kiss and four KissR genes arose from 1R and 2R early in the vertebrate lineage, followed by repeated independent gene loss events throughout vertebrate radiation. As a consequence of the independent and asynchronous losses of Kiss genes, as well as of KissR genes, the extant vertebrate species present various combinations of putative Kiss and KissR couples. For example, the same two Kiss genes (Kiss1 and Kiss2) have been conserved in a prototherian mammal (platypus) and in some teleosts (e.g. zebrafish, seabass) but together with the conservation of different receptors (KissR1 and KissR4 in platypus, versus KissR2 and KissR3 in zebrafish). Likewise, unmatching numbers of Kiss and KissR genes are present in some species, such as three Kiss genes versus four KissR genes in a basal actinopterygian, the spotted gar and a basal sarcopterygian (coelacanth), or two Kiss genes versus three KissR genes in a basal teleost, the eel (587, 592). Such variations in the putative couples between Kiss and KissR paralogs reveal a lack of maintenance and co-evolution of specific Kiss/KissR couples during vertebrate evolution. This may have been favored by the promiscuity of Kiss receptors towards various Kiss peptides, related to the high conservation of the 10 amino-acid Cterminal biologically active sequence (kisspeptin-10 or Kp-10) (398,413,561). In species where multiple Kiss and KissR paralogous genes have been conserved, differential physiological roles related to subfonctionalisation or neofunctionalisation may have emerged between paralogs.

Current studies on the role of Kiss in reproduction in non-mammalian vertebrates a-In amphibians and reptiles

In amphibians and reptiles, few functional studies are available and concern the action of kisspeptin on the gonads. In the anuran amphibian Rana esculenta, in vitro Kp-10 treatment induces testicular expression of both gpr54 and estrogen nuclear receptor α, ERα (109). In this species, ex vivo treatment of testis with Kp-10 stimulates spermatogenesis (110, 111) and upregulates the expression of testicular ERβ, gnrh 1 and 2, as well as the three types of gnrh receptors (110). All the effects of Kp-10 in amphibians are counteracted by Kp-234, a kisspeptin antagonist (109, 110). In the reptile Uta stansburiana (side-blotched lizard), intracoelomical treatment with kisspeptin up-regulates plasma testosterone levels (531).

b-In teleosts: positive and negative effects on reproduction

Even before the demonstration of colocalization of GPR54 on GnRH neurons in mammals (483), Parhar and collaborators reported that kisspeptin receptor (KissR2) localizes to hypothalamic GnRH neurons in tilapia, using laser-captured single GnRH neurons (578).

Similarly, in the cichlid fish Astatotilapia burtoni (246) and striped bass Morone saxatilis (919), GnRH1 neurons express KissR2 mRNA. In the chub mackerel Scomber japonicus, GnRH1 neurons in the preoptic area co-express KissR1, but not KissR2 (545). Kiss1 and Kiss2 neurons show differential connections with GnRH neurons in the zebrafish brain (697,732).

In agreement with the expression of KissR by GnRH neurons, effects of kisspeptins on GnRH neurons have been demonstrated in various teleost species. Kiss1 and Kiss2 peptides have opposite effects on the electrical activity of hypophysiotropic GnRH3 neurons in adult zebrafish: Kiss1 stimulates, while Kiss2 inhibits neuronal activity (915). In the striped bass Morone saxatilis, only Kiss2 (but not Kiss1) upregulates the expression of the hypophysiotropic gnrh1 by in vitro brain slices (920). In contrast, in hypothalamic explants of the half-smooth tongue sole, Wang and colleagues showed that Kiss2 has no effect on either gnrh2 or gnrh3 mRNA levels (852). In vivo studies reported either no (zebrafish gnrh 2 and 3:

(366); grouper gnrh3: (707); hybrid bass gnrh 2 and 3: (919); yellowtail kingfish gnrh1: Concerning the effect of kisspeptin on the pituitary in teleosts, direct (in vitro) stimulatory action of kisspeptin 2 (Kp2) on pituitary LH secretion was reported in goldfish (895), striped bass (918, 920) and sea bass ( 179), but no effect of Kp1 was observed in goldfish ( 413) and sea bass ( 179)). In contrast, in the European eel, heterologous and homologous Kiss peptides all directly inhibit the expression of lh, with no effect reported on fsh (588, 590). In the striped bass also, Kp1 is generally ineffective but, at high doses, can inhibit lh expression (918,920). A few studies also report a stimulatory effect of kisspeptins on FSH (striped bass, Kp1 and Kp2 (918,920); sea bass, Kp2 ( 179)). In vivo stimulatory (goldfish (413); sea bass (185); seahorse Hippocampus erectus (911)) or no (goldfish ( 524)) action of kisspeptins on gonadotropins have been described in teleosts. In the striped bass, kisspeptin action depends on the stage of development, as intramuscular injection of Kp1 has no effect on LH at the pubertal stage, while both Kp1 and Kp2 increase LH levels at gonadal recrudescence (919). In both sexes (adult immature stage) of the chub mackerel Scomber japonicus, icv administration of Kp2, but not Kp1, increases fshβ and lhβ mRNA levels (546,547).

The role of Kiss was further investigated in knocked-out fish models. Two studies reported normal fertility in KO fishes for kisspeptin-related genes (zebrafish: (768); medaka: (524)).

In KO medaka for kiss1, kiss2, gpr54-1 or gpr54-2, ovaries and testes develop normally as compared to wild-type fish, with full-grown and late-vitellogenic follicles, and spermatozoa being observed, respectively (524). There are also no significant differences in the expression levels of both lhβ and fshβ between the kisspeptin-related gene KO lines and wild-type (524).

Similarly, zebrafish with mutations for kiss1, kiss2, kissr1 or kissr2 show normal gametogenesis and reproductive capability, as well as normal expression levels of gnrh2, gnrh3, lhβ and fshβ (768). Double mutation (kiss1-/-; kiss2-/-), which prevents the compensation between ligands, causes lower expression of gnrh3, lhβ and fshβ, supporting that kisspeptin signalling stimulates the expression of these genes in zebrafish (768).

However, these decreases had no impact on the phenotypes of the fish, as normal reproductive performance was reported (768). As compared to the induction of hypogonadotropic hypogonadism in mammals by loss-of-function mutation (human) or KO (mice) of gpr54 or kiss1 KO, these observations suggest a dispensable role of Kiss in the neuroendocrine control of reproduction in teleost models (zebrafish and medaka).

Interestingly, a study readdressed this question in mice by using ablation of kisspeptin neurons or of gpr54-expressing neurons (469). Differently from KO experiments, the authors observed no impact on the timing of puberty, suggesting that kisspeptin neurons play a role in the optimization of reproductive success, by integrating various cues and relaying this information to GnRH neurons, but are dispensable for puberty onset, activation of GnRH pulses and fertility. c-Loss of kiss function in birds?

As mentioned above ( § 5.2.3 a, b), phylogenomic studies suggest that two Kiss genes (Kiss1 and Kiss2) have been inherited from the amniote ancestor. In the course of amniote evolution, Kiss 1 has likely been lost early in the bird lineage, while it has been conserved in some other sauropsids and in mammals. The existence of a Kiss2-like gene has been demonstrated in the genomes of several bird species, mallard duck, zebra finch, and rock pigeon (591). These avian Kiss2-like sequences diverge from those of other vertebrates and are not found in the genomes of chicken, falcon and parrot (591), revealing the processes of Kiss2 gene pseudogenisation and loss in the avian lineage. Together with the loss of Kiss1, these results support the absence of any functional kisspeptin in birds. Concerning Kiss receptors, two genes (KissR1 and KissR4) would have been inherited from the amniote ancestor. Synteny studies demonstrate the loss of KissR1 in the bird lineage, but cannot conclude for the presence or not of KissR4 with the current databases. Altogether, current phylogenomic analysis suggests the loss of Kiss genes in birds and a possible conservation or loss of a Kiss receptor (KissR4) (still to be found).

Immunocytochemical studies reported the presence of kisspeptin-like immunoreactive neurons in the medial preoptic nucleus of the hypothalamus in the mallard drake in close proximity to GnRH fibers and almost all these neurons co-express aromatase (658). This may correspond to the derived sequence identified in the duck even though the peptide mutations and the variations in gene structure suggest a pseudogenisation (591). Kisspeptin immunoreactivity is also observed in ovarian granulosa cells of hens (887), while genomic and syntenic analyses support the loss of Kiss in this species (591). In goose, immunoreactive kisspeptin is also detected in the ovary (granular layer and theca of the follicle) and in the plasma where concentrations vary during the reproductive cycle (295). This raises the question as to whether the detection of immunoreactive kisspeptin in birds may result from cross-reactions with other RF-amide peptides.

A few functional studies using mammalian kiss peptides have been performed in birds.

Central (icv) administration of kisspeptin-52 is able to increase plasma LH levels in the mallard drake, and pretreatment with a GnRH receptor antagonist prevented this increase in LH levels (658). Kisspeptin also increases plasma LH levels in the white-crowned sparrow (cited in ( 533)). However, in adult male chicken, human Kp-10 has an inhibitory effect, as intravenous injections of Kp-10 suppress plasma testosterone levels (847). Kisspeptin-10 treatment stimulates progesterone secretion in cultured chicken granulosa cells (887).

Repeated injections of Kp-10 advance the initiation of egg-laying in the juvenile female quail (533) by increasing lipid synthesis as well as upregulating estrogen receptor protein and lipogenic gene expression in the liver (884). In the hypothalamus, Kp-10 induces an upregulation of cgnrh-I expression and a down-regulation of gnih expression. In the pituitary, Kp-10 increases lhβ and gnrh-rII and decreases fshβ expression (533). Further studies are warranted to investigate whether these actions of heterologous kisspeptin in birds are mediated by a potential Kiss receptor (KissR4; still to be identified in birds) or by other RFamide peptide receptors.

Kiss before vertebrates

In deuterostomes, in addition to vertebrates, two other sub-phyla constitute the phylum of chordates: the urochordates and the cephalochordates. Neither kisspeptin nor kisspeptin receptors have been found in urochordates (such as ascidians). In contrast, four kisspeptin-type precursors and 16 kisspeptin-like receptors have been identified in the cephalochordate amphioxus Branchiostoma floridae (492), suggesting that multiple gene duplication events specifically targeted Kiss and KissR in this lineage. In B. floridae, one of the reported genes encodes three putative peptides, suggesting additional intra-gene duplication of peptidic sequences, while the other genes encode a single peptide (492). More recently, 27 putative KissR-like genes were identified in B. floridae (856). Further expression and functional studies were performed in the amphioxus B. japonicum on one kiss-like gene (BjkissL-2) and one kissR-like gene (Bjgpr54L-1) (856). Using qPCR and immunohistochemistry, the authors showed that BjkissL-2 mRNA and protein levels are higher in notochord/nerve cord, and especially in the anterior region of the nerve cord (cerebral vesicle) and Hatschek's pit (856).

Bjgpr54L-1 expression is predominantly observed by qPCR in the notochord/nerve cord, moderate expression is seen in the testis and ovary, and lower expression in gill, muscle, hepatic caecum and hind-gut (856). Two amphioxus peptides show functional interaction with Bjgpr54L-1, while the receptor exhibits higher affinity for zebrafish Kiss peptides (856). Amphioxus synthetic Kiss peptides induce LH release in sexually mature female zebrafish and, in amphioxus, trigger the expression of gpb5 mRNA, the glycoprotein subunit related to vertebrate glycoprotein hormones (see section 3), suggesting an ancestral role of Kiss-KissR in the neuroendocrine control of reproduction (856).

In non-chordate deuterostomes, echinodermata and hemichordata are sister phyla in a clade known as ambulacraria ( 285). The occurrence of kisspeptin-type receptors has been reported in ambulacrarian species, the sea urchin S. purpuratus (phylum echinoderms) and the acorn worm Saccoglossus kowalevskii (phylum hemichordates) (318,492). Recently, kisspeptintype precursors have also been identified in ambulacrarians, the starfish Asterias rubens, S. purpuratus and S. kowalevskii (694,695). These precursors comprise two putative kisspeptinlike peptides.

Concerning protostomes, some kisspeptin-type receptors, but not yet a peptide precursor, have been found in lophotrochozoa (mollusca and annelida) [START_REF] Cardoso | Allatostatin-type A, kisspeptin and galanin GPCRs and putative ligands as candidate regulatory factors of mantle function[END_REF]318,492). Precisely, kisspeptin-like receptors are present in mollusca, bivalvia (oysters, Crassostrea gigas and Pinctata fucata and mussel, Mytilus galloprovinciallis) and gastropoda (limpet, Lottia gigantean; slug, Aplysia californica), as well as in annelida (worm, Capitella teleta) [START_REF] Cardoso | Allatostatin-type A, kisspeptin and galanin GPCRs and putative ligands as candidate regulatory factors of mantle function[END_REF]. The occurrence of kisspeptin-like receptors in lophotrochozoan invertebrates suggests the existence of kisspeptin-like peptides in these animals.

According to Elphick and collaborators, the evolutionary ancestry of kisspeptin-type receptors can be traced back to the common ancestor of the bilaterians, but with subsequent loss in urochordate deuterostomes and ecdysozoan protostomes (for reviews: (174, 175)). However, based on phylogenic and syntenic analyses using Anopheles mosquitoes (ecdysozoan), it appears that allostatin type A receptors (AST-ARs) and KissR emerged from a common gene ancestor after the divergence of galanin receptors (GALRs) in the bilaterian genome, suggesting that invertebrate AST-ARs and ligands shared a common evolutionary origin with vertebrate kisspeptin/galanin receptors and ligands (186). 5.3.6. Kisspeptin, more related to galanin/spexin than to other RF-amide peptides Originally, the kisspeptin receptor was discovered for its high degree of sequence similarity with galanin receptors (396). Kim and collaborators found that spexin (SPX), galanin (GAL) and kisspeptin (KISS) genes are on the same reconstructed vertebrate ancestral chromosome (359). Their family genes are distributed among four 2R-generated paralogons (four linkage groups). Three linkage groups contain SPX1 and KISS2, SPX2 and GAL, and KISS3 and galanin-like peptide (GALP), respectively. The fourth linkage group has KISS1 alone. The ancestral forms of KISS, GAL and SPX are proposed to arise by local tandem duplications before 2R (Figure 9) and to expand their family members through 2R (359). Likewise, KISSRs and GALRs have probably emerged through local duplications before 2R, producing Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] three subgroups in vertebrates: KISSRs (4 KISSRs), GALR1 (GALR1a and GALR1b), and GALR2/3 (GALR2a, GALR2b and GALR3)(for review: (904). SP1 and SPX2 are functional ligands for GALR2 and GALR3 and are even more potent than GAL in activating GALR3 (359). The evolutionary origin of the KISS (farp-4)/SPX/GAL family is far distant from those of the NPFF (farp-1)/QRFP(farp-3) and PrRP(farp-2)/NPY families, so that some authors propose that kisspeptin should be classified separately (for review: ( 904)). This infers that common peptide sequences such as the C-terminal sequence shared by the RF-amide peptide super-family may reflect conservation but also convergences of peptide sequences especially suitable for bioactivity.

The galanin peptide family is constituted of galanin, galanin message-associated peptide (GMAP; encoded by the same gene as galanin), galanin-like peptide (GALP; encoded by a distinct gene) and alarin (encoded by a splice variant of GALP gene) (for review: (389)). Spexin (SPX; now renamed SPX1) was discovered in 2007 in human proteome (493). A second form, SPX2, has been characterized in all vertebrates except mammals (359). GALR2 and GALR3, but not GALR1, have been shown to be the cognate receptors for SPX (359).

Regarding functional roles of these peptides, they share an involvement in the control of reproduction, especially as a link between metabolism and reproduction, which have been previously reviewed in depth by other authors (for reviews: galanin family, (182, 478); GALP, (393); spexin, (441)).

Prolactin releasing peptide (PrRP) group (farp-2)

The search for the ligand of the human orphan pituitary receptor, hGR3, led to the identification of a new peptide from bovine hypothalamic extract that acts as a prolactinreleasing factor in rat anterior pituitary cells and was thus named prolactin releasing peptide, PrRP (280). The prepro-protein generates at least two forms of mature peptide, PrRP31 and PrRP20 (a C-terminal fragment of PrRP-31) ( 280)). At the same time, another RF-amide peptide, with a similar amino acid sequence, was isolated from the brain of a teleost, the Japanese crucian carp, and named Carassius-RFa (C-RFa) (210). C-RFa homologs have been characterized in other teleosts as well as in chicken, Xenopus and lamprey, but not in mammals, and C-RFa had been considered as a teleost PrRP (for review: (762)). However, while looking for PrRP and C-RFa in chicken, [START_REF] Wang | Identification of the receptors for prolactin-releasing peptide (PrRP) and Carassius RFamide peptide (C-RFa) in chickens[END_REF] found that PrRP and C-RFa are encoded by distinct genes in non-mammalian vertebrates, originating through duplication of an ancestral gene (386). Tachibana and Sakamoto (762) thus proposed that the widely used name of PrRP/C-RFa in lower vertebrate species be renamed PrRP2, as previously suggested by Wang and collaborators (859). (508)). In contrast, after the initial finding of Hinuma and collaborators (280), other studies in mammals questioned the role of PrRP as a prolactin releasing factor and thus led to the hypothesis that this role of PrRP may be ancient and even lost in mammals. In fact, there is now clear evidence that PrRP is involved in the control of feeding behavior and energy expenditure in mammals as well as in other vertebrates (for reviews: (154, 762)).

Several studies support a role of PrRP in the neuroendocrine control of reproduction in mammals. Icv injection of PrRP to male rats increases plasma LH, FSH and testosterone levels (684), while icv administration of an anti-rat PrRP serum causes a reduction of LH surge (283). As PrRP is not able to induce release of LH and FSH directly from dispersed male pituitary cells in vitro, but instead can increase the release of GnRH from hypothalamic explants (684), it was suggested that PrRP could stimulate gonadotropin secretion via a hypothalamic mechanism involving the release of GnRH in male rat. The control of GnRH1 neurons by PrRP in rat is further supported by the presence of PrRP fibers in the medial preoptic area and of PrRP receptors in GnRH1 neurons (187). To the best of our knowledge, no data are yet available for such a role in other vertebrates.

Phylogenetic, pharmacological and paralogon analyses reveal that prolactin releasing hormone receptor (PrRP-R) shares a common ancestry with neuropeptide Y (NPY) receptors (385). In fact, NPY binds to PrRP-R1 and inhibits response of PrRP-R1-expressing cells to PrRP, behaving as an antagonist. NPY-type peptides have an ancient origin in bilaterians as they are present both in protostomes (328) and deuterostomes. An ancestral PrRP peptide probably started coevolving with a redundant NPY receptor, which then became PrRP-R, approximately 500 Million years ago (385). The distinct PrRP/NPY family genes and their receptor genes emerged by local gene duplication during early vertebrate evolution (for review: ( 904)) (Figure 9). NPY has been largely recognized for its involvement in the interactions between food intake, metabolism and reproductive function (for reviews: (146, 473, 519)).

Conclusion on RF-amide peptides

While RF-amide peptides, which all share a conserved C-terminal RF-amide signature, have been described as a family of neuropeptides encoded by five different genes in mammals, phylogeny and synteny analyses suggest that they do not all derive from a common ancestor and perhaps should not be seen as a family.

As reviewed above, RF-amide peptides, such as GnIH and kisspeptin, are critically involved in the control of reproduction and puberty. Most RF-amide peptides (GnIH, kisspeptin, QRFP/26RFa, PrRP) and non-RF-amide peptides which they are related to, such as NPY for PrRP and galanin/spexin for kisspeptin, are also major regulators of food intake and metabolism (for reviews: (153); GnIH, kisspeptin (848) ; kisspeptin (877) ; QRFP/26RFa In the nervous system of adult vertebrates, neurotransmitters act as chemical mediators of intercellular communication by the activation of specific receptors and second messengers in postsynaptic cells. This specialized role appears to have evolved from more ancestral functions in primitive organisms where these substances were used as both intra-and intercellular signals. Indeed, a number of 'classical' neurotransmitters are present in primitive organisms and early embryos in the absence of a nervous system [START_REF] Buznikov | From oocyte to neuron: do neurotransmitters function in the same way throughout development?[END_REF] and it has been suggested that these molecules "initially functioned as intracellular regulators, then became local hormones, and finally acquired the role of synaptic transmitters" [START_REF] Buznikov | Changes in the physiological roles of neurotransmitters during individual development[END_REF]811).

It is now clear that in vertebrates, that most known central nervous system neurotransmitter substances may also participate in the regulation of pituitary secretion and that in some instances "neurotransmitters" behave like releasing hormones. The best example is dopamine (DA) which, in mammals, is released from nerve endings of tuberoinfundibular DA (TIDA) neurons in the median eminence and pituitary stalk to activate DA receptors at the pituitary level after being transported there by portal blood vessels. Hence, the definitions of neurotransmitters and neurohormones are partially intermingled (810). Neurotransmitters can participate in the control of pituitary secretion by serving as a neurotransmitter input, or releasing factor output, of hypothalamic neuroendocrine transducer cells; they can act also within these cells, or act as neurotransmitter within a nerve tract that impinges upon the hypothalamus [START_REF] Wurtman | Brain monoamines and endocrine function[END_REF].

a-Monoamines

Monoamines (such as catecholamines, serotonin, histamine) are evolutionary ancient molecules. They are present in metazoa and also in some protozoa (811). They control neural and endocrine systems in both non-vertebrates and vertebrates. In vertebrates, physiological and pharmacological evidences make it clear that monoamines are involved in the regulation of anterior pituitary hormone secretion, including gonadotropins (LH and FSH).

85

-The catecholamines, dopamine (DA), norepinephrine (NE) and epinephrine (E) are major neurotransmitters found in most, if not all, metazoan species, although the nature of the catecholamines may differ between animal phyla. Their role as neuromediators or neurohormones is documented in a limited number of species: While the neuromodulatory functions of DA appears to be conserved in all bilaterians (505), that of NE is clearly demonstrated only in vertebrates. In mammals, both have been implicated in the regulation of GnRH secretion (222,339).

-The indoleamine, serotonin (5-hydroxytryptamine; 5-HT), first identified as a neurotransmitter-signaling molecule in mammals, is ubiquitous across all forms of life. Cellscontaining 5-HT have been found in representatives from all major metazoan clades, e.g., cnidarians, plathyhelminths, nematodes, arthropods, annelids, mollusks, echinoderms, tunicates and vertebrates [START_REF] Azmitia | Serotonin and brain: evolution, neuroplasticity, and homeostasis[END_REF]137,268) suggesting an early appearance during animal evolution. As regards reproductive functions, various studies in vertebrates have demonstrated a role of 5-HT in the secretion of reproductive neurohormones and sexual behaviors (for review (621)).

-Histamine (HA): Classically established as a "peripherally" important mediator of inflammation, HA is now accepted to play a role in neurotransmission (254). The brain histaminergic system is a phylogenetically old group of neurons that project to most regions of the central nervous system (253). b-GABA GABA (gamma amino butyric acid) is known as the main inhibitory neurotransmitter in the brains of mammals (144). Such a function appears ancestrally derived, as GABA exerts similar inhibitory functions in the nervous system of even the most primitive animals (238).

GABA plays a key role in the control of pituitary hormone release, including gonadotropins, in mammals (414, 839) as in fish (799). The first step in catecholamine and indoleamine biosynthesis is the ring hydroxylation of the aromatic amino acid substrates (tyrosine or tryptophan respectively) catalysed by a class of rate-limiting enzymes, the aromatic amino acid hydroxylases (AAAH). These proteins belong to a family of tetrahydrobiopterin (BH4)-dependent monooxygenases, which in vertebrates includes one phenylalanine hydroxylase (PAH), two tyrosine hydroxylases (TH1 and TH2) and two tryptophan hydroxylases (TPH1 and TPH2).

AAAHs are present in phylogenetically distant taxonomic groups such as bacteria, insects and mammals [START_REF] Cao | Phylogenetic analysis and evolution of aromatic amino acid hydroxylase[END_REF]. The TH, TPH, and PAH genes are found in all sequenced genomes of bilaterians, supporting the presence of each of the AAAH family members long before the divergence of chordates (595). Phylogenetic studies suggest that the AAAHs originated by duplication and divergence of a common ancestral gene at the base of the eukaryotic tree. Some lineage-specific intron loss or gain events have occurred during the expansion of AAAH genes and generated diversity of gene structures [START_REF] Cao | Phylogenetic analysis and evolution of aromatic amino acid hydroxylase[END_REF]. The high level of sequence identity between different subfamilies suggests evolutionary conserved functions.

In eukaryotes, these enzymes are composed of a homologous central catalytic domain to which is attached discrete N-terminal regulatory domains and a short C-terminal tetramerization domain, whereas the bacterial enzymes lack the N-and C-terminal domains. Therefore it is believed that the C-terminal portions of all three enzymes arised from a common ancestor, and represent the catalytic core (243) while the amino terminal regions are responsible for substrate specificity. The eukaryotic hydroxylases are all homotetramers (see (195,773).

-TH catalyzes the hydroxylation of tyrosine to L-dihydroxyphenylalanine (L-DOPA), the first and rate-limiting step in the biosynthesis of catecholamine neurotransmitters DA, NE and E (409). Two paralogous genes encoding TH are found in teleost fishes, amphibians, birds and non-eutherian mammals. They emerged as a consequence of a WGD which occurred before the divergence of jawed vertebrates (probably 2R-WGD), but TH2 was secondarily lost in eutherian mammals (893). The history of TH gene evolution within vertebrates may be also shared by the other AAAH ( 893).

-TPH catalyzes the hydroxylation of tryptophan to 5-hydroxytryptophan, the first and rate-limiting step in the biosynthesis of serotonin (321).Two distinct molecular isoforms of TPH, TPH1 and TPH2, resulting from a whole genome duplication (WGD) which occurred in the vertebrate lineage, are present in the brains of zebrafish [START_REF] Bellipanni | Cloning of two tryptophan hydroxylase genes expressed in the diencephalon of the developing zebrafish brain[END_REF] as well as humans, mice and rats (851). The TPH isoform discovered first is referred to as TPH1 and is primarily found in the pineal gland of mammals (243,421). By contrast, the second TPH isoform, TPH2 first cloned from the rat pineal gland ( 139) is strongly expressed in 5-HT-producing neurons of the raphe nucleus in mammals (593, 851), and also of the hypothalamus in teleosts (632).

Sequence homology analysis of vertebrate TPHs indicates that the sequence identity between TPH1 and TPH2 within a species is low, whereas the sequence identities between TPH1s or TPH2s from different species are relatively high. While two TPH genes (tph1 and tph2), are found in most groups of jawed vertebrates, in teleost fishes (for instance, in zebrafish, stickleback and medaka) three paralogs (tph1a, tph1b and tph2) that likely result from the teleost-specific whole genome duplication (TWGD), have been described (for review (421)).

b-Amino acid decarboxylases (ADC)

The aromatic amino acid decarboxylase (AADC), also called DOPA decarboxylase, is encoded by the ddc gene, and transforms L-DOPA into DA. AADC also transforms 5-HTP into 5-HT. AADC is a member of the large family of decarboxylases which include other enzymes involved in the synthesis of neurotransmitters, such as histidine decarboxylase (HDC) for histamine and glutamate decarboxylase (GAD) for GABA (651). HDC is highly conserved throughout metazoa (254). AADC is present in both protostomes and deuterostomes, suggesting its presence in ancestral bilaterians. AADC has been duplicated in insects leading to two paralogous genes (ddc and amd). In mammals, alternative splicing generates various ddc transcripts, one being specific to the nervous system (894).

Glutamic acid decarboxylase (GAD) catalyzes the decarboxylation of glutamate, the (single and) rate-limiting step in the biosynthesis of GABA. Throughout the vertebrate taxa, GAD exists as two major isoforms, GAD65 and GAD67 (for review (799)). They are thought to derive from 2 paralogous genes that arose in early vertebrates at least in a gnathostome ancestor as both GAD65 and GAD67 paralogs have been cloned from two chondrichtyan species; in contrast a single GAD appears to be present in non-vertebrate chordates, urochordates (ascidians) an cephalochordates (amphioxus) in which the GAD sequence are highly divergent [START_REF] Bosma | Multiplicity of glutamic acid decarboxylases (GAD) in vertebrates: molecular phylogeny and evidence for a new GAD paralog[END_REF]391). There is also evidence for a third GAD gene in a teleost, the armoured grenadier, although this paralog does not classify with either GAD 65 or 67. It is found throughout the grenadier brain including the hypothalamus but its importance there remains unexplored (799).

Origin and evolution of neuromediator receptors: direct phylogeny

Neurotransmitter receptors are critical elements in intercellular signaling within the central nervous system and are divided into two major types, based on their molecular structure and biophysical properties. a-G-protein-coupled receptors (GPCRs) Most of, if not all, the physiological actions of catecholamines, indolamines and histamine, as well as some actions of GABA (via GABA B receptors) are mediated by receptors which belong to the largest membrane protein family known so far, the seven transmembrane (7-TM) segment receptors coupled to heterotrimeric G-protein (G-protein-coupled receptors or GPCRs). This family of receptors transmits the effect of agonist binding to the various intracellular effectors by interacting with an intermediary G-protein (532). The diversity of receptor subtypes inside this neurotransmitter receptor superfamily, observed in many animal species, is the result of a long and complex evolutionary process consisting in gene duplications and continuous accumulation of mutations. GPCRs are believed to have evolved through a series of gene duplication and divergence events that started with a single ancestral gene (209): the first event was the divergence of the catecholamine receptors from the muscarinic acetylcholine receptors, which occurred prior to the divergence between deuterostomes and protostomes, since they are present at least in arthropod and vertebrate lineages. Subsequently, the ability to activate specific second-messenger pathways diverged independently in both the muscarinic and the catecholamine receptors (209).

The calculation of phylogenetical distances between bioamine receptors revealed two main periods of diversification: the first one likely occurred in the Precambrian before the separation between the protostomes and deuterostomes and corresponds to the appearance of the main subtypes of bioamine receptors. The second one, might have accompanied the cephalization of the CNS in vertebrates (836).

b-Ligand-gated ion channels

Ligand-gated ion channels, also called ionotropic receptors, are transmembrane ion-channel proteins, which after binding of their ligands, allow the passing through of permeant ions (such as sodium, potassium, chloride and calcium), leading to changes in membrane potential. This superfamily of proteins is found in almost all forms of life (238), with strong structural similarities despite the variety in ions gated and in ligands (850). Two subtypes of GABA receptors (GABA A and GABA C ) and the subtype 3 of serotonin (5-HT3) receptors are members of this superfamily. They are composed of five homologous subunits. Evolutionary scenario of the family of GABA A and glycine-like receptors (GRL), suggests the presence of an ancestral receptor in bilateria and that a set of local gene duplications, WGD rounds in early vertebrates (1 R and 2 R) and gene loss led to current set of GLR subunits in extant vertebrates including human (803).

6.2.

A key-neuromediator: dopamine 6.2.1. Major brain neuromediator in human and other mammals Dopamine (DA) is a neurotransmitter broadly distributed in the vertebrate central nervous system (CNS) (311). After its discovery as a neurotransmitter in the CNS of vertebrates ((88, 89), DA has raised large interest for its various roles in brain functions and its involvement in severe human pathologies. DA systems regulate sensory perception, motor function, memory, emotion, food intake, and various hypothalamic functions including the neuroendocrine control of pituitary hormones. Pathologies related to the multiple functions of DA include Parkinson's disease (291), schizophrenia, Tourette Syndrome, addiction to drugs, and pituitary adenoma (for reviews [START_REF] Björklund | Dopamine neuron systems in the brain: an update[END_REF]311,681)). The involvement of DA in diverse brain functions is ensured by independent dopaminergic systems (894). a -Multiple brain dopaminergic systems; multiple brain functions; multiple receptors Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

The dopamine systems in vertebrates are highly diversified anatomically and also molecularly as regards DA biosynthesis enzymes and receptors. Gene duplications and losses have contributed to this diversification (891-893). The mammalian brain contains ten neuroanatomically distinct dopaminergic systems (named A8 to A17) located in the forebrain and midbrain [START_REF] Björklund | Dopamine-containing systems in the CNS[END_REF]. The (A8-A10) DA neurons are involved in initiation of movement and behavioral responses as well as in drug addiction. The A11 DA neurons are involved in autonomic motor regulation, and the A12-A15 neurons in neuroendocrine regulation. The A16 DA cell bodies in the olfactory bulb and A17 in the retina are involved in olfactory and visual perceptions, respectively [START_REF] Björklund | Dopamine neuron systems in the brain: an update[END_REF][START_REF] Björklund | Dopamine-containing systems in the CNS[END_REF]724). Comparative anatomical and functional studies highlight both conservation and divergences of DA forebrain and midbrain systems across vertebrates (345,724,894).

The pleiotropic activity of DA also relies on a diversity of receptors. DA exerts its actions on target cells by activating specific membrane receptors belonging to two structurally and functionally different classes of GPCRs, termed D1 and D2, and originally distinguished by their ability to activate (D1 class) or inhibit (D2 class) adenylate cyclase (351). D1 and D2 receptors also regulate other signal transduction pathways including calcium and potassium channels and arachidonic acid synthesis [reviewed in (314, 494, 712, 828) Each class of DA receptors comprises two to five subtypes depending on the vertebrate species: in mammals, the D1 class comprises two receptor subtypes (D1 and D5), while the D2 class comprises three receptor subtypes (D2, D3 and D4). However, in non-mammalian species, additional DA receptor genes have been found. Phylogenetic analyses strongly suggest that the common ancestor of Osteichthyans possessed four subtypes in the D1-class (D1, D5, D6 and D7), and five subtypes in the D2-class (D2, D3, D4, D8/D2 l and D9/D4 rs ;

(891, 892). While multiple gene losses have largely reduced the number of DA receptors in mammals, many DA receptor genes have been conserved in other vertebrates; moreover, teleost-specific WGD (3R) further increased the number of DA receptor genes in this lineage (891).

Notably, D1 and D2 DA receptors are phylogenetically not more related to each other than to other monoamine receptors [START_REF] Callier | Evolution and cell biology of dopamine receptors in vertebrates[END_REF]131,892). This suggests that the ability to bind DA, shared by the two receptor classes, was acquired independently reflecting a convergence process during metazoan evolution. b-Neuroendocrine functions (e.g. major inhibitory regulator of pituitary prolactin via dopamine D2 receptors)

In mammals, DA represents the major nonpeptidergic agent exhibiting well-defined neuroendocrine functions and its role as an inhibitor of pituitary lactotroph cell secretion became recognized in the 1970s: based on the evidence of dopaminergic nerve terminals in the median eminence (215), McLeod and coworkers (445) proposed that DA may be released into the pituitary portal system, and thereby act as a hypothalamic hormone (distinct from its neurotransmitter role in other systems). They demonstrated that dopaminergic agonists were effective at suppressing prolactin (PRL) secretion in vivo, and in vitro from isolated pituitary glands (445). DA was subsequently detected in the pituitary portal blood (340), and variations of DA levels in the portal blood were shown to account for changes in PRL secretion in Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] various physiological conditions [START_REF] Ben-Jonathan | Dopamine in hypophysial portal blood: relationship to circulating prolactin in pregnant and lactating rats[END_REF][START_REF] Ben-Jonathan | Dopamine in hypophysial portal plasma of the rat during the estrous cycle and throughout pregnancy[END_REF]229,242). DA receptors of the D2 class were identified on anterior pituitary lactotroph cells (453). Finally, the observation that mice lacking the DA D2 receptor are hyperprolactinemic (352,652), clearly demonstrated the critical role of DA in suppressing endogenous PRL secretion. Interestingly, in all hormonal systems studied so far, whether at the hypothalamic, posterior pituitary, or anterior pituitary level, DA functions as an inhibitor via DA receptors of the D2 class (for reviews [START_REF] Ben-Jonathan | Dopamine as a prolactin (PRL) inhibitor[END_REF]241)).

While DA is now established as the primary regulator of PRL gene expression and release in both mammals and teleost fish [START_REF] Ben-Jonathan | Dopamine as a prolactin (PRL) inhibitor[END_REF]241,872), it also exerts some negative control on the release of growth hormone (GH), thyroid-stimulating hormone (TSH) and melanocytestimulating hormone (α-MSH) (for review (810)) in the pituitary of both mammals and teleost fish, despite differences in the neuroanatomical organization of the hypothalamo-pituitary axis between these vertebrate classes [START_REF] Ball | Hypothalamic control of the pars distalis in fishes, amphibians, and reptiles[END_REF]. An additional neuroendocrine action of DA, initially discovered in teleosts and later demonstrated in various vertebrate species, is the inhibitory control of gonadotropin secretion and reproductive function ((168, 603); see section 6.2.4). 6.2.2. Evolution of tyrosine hydroxylase, key-enzyme of dopamine synthesis a-Biosynthetic pathway of dopamine Dopamine is synthesized from the aromatic amino acid tyrosine through two enzymatic steps.

The first and limiting step is catalyzed by an aromatic amino acid hydroxylase (tyrosine hydroxylase [TH]), and the second step by the aromatic amino acid decarboxylase (AADC), often called DOPA-decarboxylase. TH, as the other AAAHs, has at least one homolog in all bilaterian species studied so far. TH probably evolved from an ancestral AAAH that did not have a regulatory domain and gave rise to all three present-day AAAH (394).

b-Tyrosine hydroxylase 1 and 2 in vertebrates

The gene coding TH has been identified in species of several vertebrate groups, including humans (521), rats (244), mice (301), bovines (136), quails (184), chicken [START_REF] Carrier | Chicken tyrosine hydroxylase gene: isolation and functional characterization of the 5' flanking region[END_REF] and lamprey [START_REF] Barreiro-Iglesias | The sea lamprey tyrosine hydroxylase: cDNA cloning and in situ hybridization study in the brain[END_REF]. Whereas only one gene encodes TH in mammals (with two to four proteic isoforms generated by alternative splicing), two non-allelic TH genes (th1 and th2) exist in several teleost species [START_REF] Candy | Two tyrosine hydroxylase genes in teleosts[END_REF]. Phylogenetic analyses showed that both th1 and th2 genes are not only found in teleosts but also in all studied non-eutherian vertebrates, therefore in all vertebrates except placental mammals (893). It is thus likely that the ancestral vertebrates possessed TH1 and TH2 DA-synthesizing cells.

The existence of two paralogous TH genes in teleost fishes, amphibians, birds and noneutherian mammals suggests that the gene duplication giving rise to the two TH genes is ancient in the vertebrate lineage [START_REF] Barreiro-Iglesias | The sea lamprey tyrosine hydroxylase: cDNA cloning and in situ hybridization study in the brain[END_REF] probably as a consequence of the second round (2R) of WGD (548,575,713). While TH2 is still found in prototherian (platypus) and metatherian mammals (opossum), it may have been lost in the eutherian mammalian lineage which possess a single TH, TH1 (893). Genomes of many eutherians are fully sequenced, and the chromosomal localizations of the TH genes and their syntenic genes support the loss of TH2 in the eutherian mammals. Indeed, apart from the absence of TH2 in the eutherian mammals, the order of the neighbouring genes (IGF1, PAH, and ASCL1) at the locus is highly conserved.

c-Tyrosine hydroxylase in metazoa

Tyrosine hydroxylation, and its regulation, is an ancient and critical biochemical pathway.

The hydroxylation of tyrosine to form L-3, 4-dihydroxyphenylalanine is an enzymatic pathway utilized not only throughout animal phyla but in plants as well. TH, as the other AAAH, has at least one homolog in all bilaterian species studied so far (505).

The gene coding TH has been identified from various species of non-vertebrates, including schrimps (454), fresh water crab (D pagei; (615)), parasitic helminthes (Schistosoma mansoni (258); Schistosoma japonicum (294),and insects,[Drosophila (760); moth (300); cricket (862)]. In several species of insects, as in mammals, different isoforms of TH produced by alternative splicing have been identified (in the cricket (862), in D. melanogaster and the armyworm M. separata [START_REF] Birman | A novel and major isoform of tyrosine hydroxylase in Drosophila is generated by alternative RNA processing[END_REF]534). Since the drosophila TH protein exhibits similar kinetic parameters and regulatory mechanisms to its mammalian counterpart, it is likely that very strong evolutionary constraints have been placed on the biochemical mechanism (529). The number of DA receptors subtypes has been multiplied by the two major rounds (1R/2R) of WGD that took place in early vertebrates (286,296,438). Additional duplication of DA receptor gene occurred in the teleost fish lineage via TWGD (3R) [START_REF] Amores | Zebrafish hox clusters and vertebrate genome evolution[END_REF]316,617,772). Duplicated paralogous genes were maintained in some vertebrate groups, probably by the acquisition of some differential functional properties, specific of each subtypes, as well as by discrete changes in their expression patterns in the brain (for reviews (861,862)).

b-Multiple genes in teleosts

Five subtypes of D2 receptor genes (D2, D3, D4, D8 (also named D2 l for D2 like ) and D9 (also named D4 -rs for D4-related sequence) exist in teleosts. The D2 l and D4 rs genes would have originated in the ancestor of gnathostomes (562). Phylogenetic analyses strongly suggest that the ancestral Osteichthyes (bony jawed vertebrates) possessed five D2-class of DA receptors (D2, D3, D4, D8 and D9) likely resulting from 1R/2R with a possible additional specific duplication (891,892). In eutherian mammals, only three D2-class DA receptors are found (D2, D3, D4) due to multiple DA receptor gene loss in this lineage (891). In contrast, up to seven D2 class DA receptors (D2a, D2b, D8, D3, D4a, D4b, D9) have been identified in the zebrafish [START_REF] Boehmler | D4 Dopamine receptor genes of zebrafish and effects of the antipsychotic clozapine on larval swimming behaviour[END_REF][START_REF] Boehmler | Evolution and expression of D2 and D3 dopamine receptor genes in zebrafish[END_REF]891), the additional receptors (D2a/D2b, D4a/D4b) likely resulting from TWGD.

Dopamine as a major inhibitory regulator of gonadotropin secretion in teleosts

A major neuroendocrine action of DA, initially discovered in teleosts and later demonstrated in various vertebrate species, is the inhibitory control of gonadotropin secretion and reproductive function (167,168,603). This inhibitory role of DA appears to be a powerful counterpart to the well-known stimulatory role of GnRH in the neuroendocrine control of reproduction.

a-Discovery in goldfish

The discovery by Peter and colleagues, using brain lesion approaches, of the presence of a gonadotropin release-inhibiting factor (GRIF (604)) in the hypothalamus of goldfish has been previously reviewed (167). GRIF neurons were subsequently shown to originate from the preoptic area (POA) and project to the pituitary (606). In vivo experiments aimed at investigating the effect of various DAergic agonists and antagonists on LH secretion and ovulation strongly suggested that DA could be the GRIF (100). Immunocytochemical and neuroanatomical studies supported this conclusion by revealing DA cell bodies in a specific Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] region of the POA, the nucleus preopticus anteroventralis (NPOav), with projections in the proximal pars distalis of the pituitary where gonadotrope cells are located (333,606). Lesions of the NPOav induce a surge of LH and subsequent ovulation (336). Finally, in vitro studies on primary cultures of goldfish pituitary cells revealed that DA inhibits both basal and GnRHstimulated LH release by acting directly on gonadotropes, through binding to receptors pharmacologically-related to the mammalian D2 receptors (101). In addition, in goldfish, DA exerts inhibitory effects on GnRH neurons, blocking the synthesis of the peptide or its release from the pituitary nerve terminals (602,901). The discovery of a dual control of reproduction led to a major application in aquaculture: the development of a spawning induction method based on combinated treatments with a DA antagonist and a GnRH agonist that has been widely used to induce spawning in captivity of a certain number of species (LINPE method, named after the scientists R. Peter and HR Lin (for review ( 603)).

b-Evidence in various teleosts

As a matter of fact, the role of DA as a GRIF, originally demonstrated in the goldfish, a cyprinid, has been later on observed in various other teleost species, including other cyprinids, but also in species belonging to other teleost subgroups such as silurids, salmonids, percomorphs, mugiliforms, elopomorphs (for review (167)) and pleuronectiforms (251).

In some teleost species, however, this physiological role of DA was not found (for review (168)). It is worth noting that the intensity of the dopaminergic inhibition varies according to the species, from a drastic barrier in cyprinids (603,605) or in prepubertal eel (166, 837) to a milder control in salmonids (659).

As in the goldfish, DA actions on gonadotrope cells are mediated by receptors of the D2 class in all species studied (European eel (326,838), tilapia (408) catfish [START_REF] Van Asselt | Characterization of dopamine D2 receptors in the pituitary of the African catfish, Clarias gariepinus[END_REF], grey mullet [START_REF] Aizen | Enhancing spawning in the grey mullet (Mugil cephalus) by removal of dopaminergic inhibition[END_REF] and zebrafish ( 202)). In zebrafish, ISH and ICC studies reveal that the TWGD-paralogs D2a and D2b as well as D8 are expressed in LH-producing cells, suggesting that the three receptors are involved in mediating DA inhibitory control in this teleost (202). In the eel, the TWGDparalog D2b is predominantly expressed as compared to D2a in LH and FSH cells (326). The expression of D2a and D2b is differentially regulated by sex steroids (585) and the two receptor subtypes are differentially involved in the onset of puberty (319). These data suggested a functional differenciation of the TGWD-D2 paralogs in the eel, with a major role of the D2b receptor in the control of gonadotropic function (326).

Dopamine as an inhibitory regulator of gonadotropic axis in other vertebrates

A dopaminergic inhibition of GnRH-induced pituitary gonadotropin secretion has also been found in a chondrostean fish, the white sturgeon (Acipenser transmontanus; (596)). This indicates that the role of DA in the inhibitory control of reproduction may have a more ancient evolutionary origin, in an actinopterygian ancestor, common to teleostean and chondrostean fishes.

The inhibitory influence of DA on gonadotropin secretion and reproduction is not restricted to fish (584, 837): A dopaminergic inhibitory control of reproduction has been shown also in representative species of various other classes of tetrapods as demonstrated in amphibians, birds, and mammals (for review (168)).

In amphibians, some data point to an important role for dopaminergic inhibition in the regulation of seasonal reproduction. In the frog, Rana temporaria, lesions of the infundibular hypothalamus in hibernating preovulatory females cause advanced ovulation (734,735). This effect is mimicked by a dopaminergic antagonist and blocked by administration of a dopaminergic agonist (736). More recent studies indicate that the inhibitory effects of DA on reproduction are conserved in frogs: for instance, in the wood frog, injection of quinpirole in females delays or inhibits oviposition (844). The release of sperm and eggs is induced in several anurans and salamanders by the co-injection of a GnRH agonist and the selective DA receptor D2 antagonist metoclopramide (termed "the amphiplex method" (121,240,795,796,845). The technique has also been successfully applied in small-scale trials to several other amphibian species (796).

In birds, there is similar evidence for an inhibitory role of DA on reproduction (for review (168)). For instance, in laying hens, the anovulatory state induced by food withdrawal, is caused by a dopaminergic inhibition of GnRH release at the median eminence level, where a dense concentrations of DA and GnRH-containing processes is observed, providing opportunities for synaptic interactions between them (128).

In mammals, DA is involved in the modulation of pulsatile LH release in some species. This effect has been extensively studied in seasonal mammals notably in sheep, in which DA participates in the inhibition of gonadotropic activity before puberty [START_REF] Brango | A role for catecholaminergic neurons in the suppression of pulsatile luteinizing hormone secretion in the prepubertal ewe lamb[END_REF] as well as in adults during seasonal anestrus (for reviews (221,781)) by acting on GnRH neurons at the median eminence level (379), through D2 receptors [START_REF] Bertrand | Implication of D2-like dopaminergic receptors in the median eminence during the establishment of long-day inhibition of LH secretion in the ewe[END_REF]. In rat, GnRH neurons are directly innervated by catecholamine terminals, including DA ones (106), but the participation of the dopaminergic system in the control of FSH and LH release remains controversial in adults since raising brain DA activity can either inhibit [START_REF] Beck | Increased sensitivity of dopaminergic inhibition of luteinizing hormone release in immature and castrated female rats[END_REF]130,222,432) or stimulate (412,444) gonadotropin release. By contrast, in the developing rat, DA clearly exerts an inhibitory control on both LH and FSH secretion during the second and third weeks of female life, by influencing GnRH release into the portal blood (384). In some other species, a direct inhibitory effects of DA on LH release at the pituitary level has been reported: for instance, in rabbits, DA injected intravenously inhibits GnRH-stimulated LH secretion in normal and also in stalk-sectioned animals (138). Finally, in humans, several observations suggest that a direct inhibition by DA on LH release may occur under physiological and pathological conditions. For instance in men, infusion of DA (which does not cross the blood-brain barrier) significantly decreases circulating LH levels and attenuates the LH release in response to a Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] bolus of GnRH (299). This DA-induced inhibition of LH secretion is associated with a reduction in both pulse frequency and amplitude of LH secretion. Further, the observation that partial inhibition of LH secretion occurs even in the presence of constant GnRH and DA infusion suggests that DA may also modulate the gonadotrope response to GnRH. In women with functional hypothalamic amenorrhea (FHA), a reduction of LH pulse frequency (and of PRL concentrations) has been documented, which can be reversed by a DA receptor blocker.

In this case, however, a hypothalamic site of DA action was inferred, through inhibition of GnRH pulse frequency [START_REF] Berga | Acceleration of luteinizing hormone pulse frequency in functional hypothalamic Downloaded from www[END_REF].

Recently, in male and female mouse, DA has been shown as the most potent inhibitor of GnRH neuron excitability: using a variety of electrophysiological approaches, the authors demonstrated that approximately around half of all GnRH neurons are inhibited by DA through D1 and D2 receptors, and that the inhibition exerted by DA on GnRH neurons is independent on gonadal steroid status (430).

In summary, DA acts as an inhibitor of reproduction in representatives of all classes of vertebrates, but this role has been differentially conserved throughout vertebrate evolution. This may either reflect an ancient regulatory pathway, common to actynopterygian (chondrosts and teleosts) and sarcopterygian (tetrapods) species, or result from convergent recruitments of DA neurons for the inhibition of reproduction in various vertebrate taxa (167).

The recruitment of DA neurons for exerting similar functions in different vertebrates suggests that DA neurotransmission may be especially suitable for the neuroendocrine inhibitory control of reproduction.

Dopamine as an inhibitor of reproduction in other metazoan

The inhibitory role of DA in the control of reproduction may be more ancient than the origin of vertebrates. Indeed, a few studies have reported an inhibitory action of DA on reproductive function in some non-vertebrate species. For example, DA inhibits the growth and maturation of oocytes in an echinoderm, the sea urchin Strongylocentrotus nudus (358). It is thus likely that this control was present in the ancestor of deuterostomes. In protostomes, an inhibitory effect of DA on reproduction has been reported both in some ecdysozoans (such as insects, crustaceans, nematodes) and lophotrochozoans (such as mollusks). In insects, DA levels are constantly maintained at a high level in the hemolymph during diapauses (308,537,538), and change with the photoperiod (115). In particular, DA is clearly a key factor for the induction of egg diapause of the silkworm, Bombyx mori (537). In crustaceans, there is evidence for a dopaminergic inhibition of testicular maturation in the fiddler crab, Uca pugilutor (666) and in the red swamp crayfish, Procambarus clarkii (668). Similarly, in the giant freshwater prawn, Macrobrachium rosenbergii, DA inhibits testicular maturation (711) and inhibits vitellogenin synthesis and ovarian maturation by inhibiting the release of vitellogenesisstimulating hormone (VHS) from the thoracic ganglia (107, 787). In a nematode, Caenorhabditis elegans, genetic and pharmacological analyses reveal that a dopaminergic pathway, acting through a D2-like DA receptor (755), inhibits egg laying (865). In a mollusk, zebra mussel, DA has been shown to reduce the intensity of .

It is thus likely that inhibitory actions of DA on reproductive functions occurred in the bilaterian ancestor and even possibly predate the emergence of bilateria, since even in a cnidarian, the coral Acropora tenuis, DA was reported to have an inhibitory effect on spawning (310).

Therefore, although its physiological functions appear to differ among species, DA plays multiple roles in suppressing the reproductive events in a number of non-vertebrate species (Figure 12).

Many other neuromediators involved in the control of reproduction

A variety of actors in mammals: Among neurotransmitters, that have been reported to also influence LH release and play a role in the control of reproduction, are found NE, 5-HT, HA as well as GABA. 6.3.1. Norepinephrine (NE) a-In mammals Sawyer and colleagues gave the first evidence that noradrenergic neurons may participate in the control of the gonadotropic axis, by demonstrating that α-adrenergic receptor antagonist blocks ovulation in rabbits (676). Further studies by various laboratories reported that NE may modulate plasma LH levels by regulating the activity of GnRH neurons (for review [START_REF] Barraclough | The Role of Catecholamines in the Regulation of Pituitary Luteinizing Hormone and Follicle-Stimulating Hormone Secretion[END_REF].

However, the idea that NE was essential for triggering of the preovulatory release of LH [START_REF] Barraclough | The Role of Catecholamines in the Regulation of Pituitary Luteinizing Hormone and Follicle-Stimulating Hormone Secretion[END_REF] has been challenged by experiments in rodents (120, 675), and in primates (369, 376),

showing that chronic interruption of the noradrenergic afferents to the hypothalamus does not impair normal ovulation. This strongly suggests that the noradrenergic system, far from being essential, exerts a modulatory action on gonadotropin secretion. It is now accepted that NE has a permissive action within the network of afferences to GnRH neurons, which may be modulated by sex steroid levels (275).

b-In other vertebrates

The role of NE in the control of reproduction has also been investigated in other vertebrates.

In birds, existing evidence suggests a role for NE in the neuroendocrine control of LH release.

The avian median eminence is known to be well supplied with NE fibers and terminals [START_REF] Calas | Radioautographic studies of aminergic neurons terminating in the median eminence[END_REF]701), and the α-adrenoreceptor blocking drug, dibenamine, has been early shown to suppresses ovulation in the hen (786). Specific blockade of NE synthesis prevents ovulation in the laying hen (867) and causes a decline in plasma concentrations of LH in young and adult male domestic fowl [START_REF] Buonomo | Aminergic involvement in the control of luteinizing hormone secretion in the domestic fowl[END_REF][START_REF] Buonomo | Pharmacological studies on the noradrenergic control of luteinizing hormone secretion in the domestic fowl[END_REF]. In vitro, GnRH secretion from chicken hypothalamuspreoptic area slices (410) or from Japanese quail hypothalamus explants ( 486) is significantly elevated in the presence of NE or β adrenergic agonists. However, icv administration of NE in laying and non-laying turkeys has no effect on LH secretion (262). In non-laying geese, noradrenergic stimulation is involved in the control of LH secretion, probably through GnRH neurons (897). In the Chinese geese (Anas cygnoides), the expression of DBH (the enzyme catalyzing the transformation of DA into NE) undergoes marked periodic variations in reproductive and endocrine tissues during the reproductive cycle (890). In the Japanese quail, a noradrenergic pathway is involved in the control of LH release through a modulation of GnIH gene expression in the hypothalamus (789).

In teleosts, NE appears to play only a slight stimulatory role on gonadotropin secretion, by acting either directly on gonadotrope cells, via α 1 -like adrenergic receptors [START_REF] Chang | Influences of Norepinephrine, and Adrenergic Agonists and Antagonists on Gonadotropin Secretion from Dispersed Pituitary Cells of Goldfish, Carassius auratus[END_REF] or on hypothalamic GnRH neurons to stimulate the release of GnRH (607,902). In fish, as in mammals, the effectiveness of NE is dependent on the stage of gonadal development: e.g. in goldfish, NE stimulates LH release mainly during gonadal regression [START_REF] Chang | Influences of Norepinephrine, and Adrenergic Agonists and Antagonists on Gonadotropin Secretion from Dispersed Pituitary Cells of Goldfish, Carassius auratus[END_REF]603). Collectively, data reveal the recruitment of NE signalling in the control of reproduction both in protostomes in deuterostomes, as well as in cnidaria, before the emergence of bilateria.

(Figure 12).

Serotonin (5-HT) a-In mammals

There is strong pharmacological evidence for a role of 5-HT in the regulation of hypothalamo-pituitary-gonadal axis, through an action either on GnRH neurons or on gonadotrope cells. Actually, 5-HT neurons located in the raphe region may play inhibitory roles in gonadotropin secretion: the pharmacological elevation of hypothalamic 5-HT levels with monoamine oxidase inhibitors suppress spontaneous ovulation in rats (383) and in vitro, 5-HT significantly inhibits the release of GnRH from the mediobasal hypothalamus of male rats (Charli et al, 1978). In sheep (155) and rabbits (624), infusion of 5-HT into the mediobasal hypothalamus blocks the ovulatory discharge of LH and ovulation. On the other hand, several lines of evidence support a permissive or facilitatory role for 5-HT in ovulation: inhibition of 5-HT synthesis with PCPA, suppresses ovulation in rats (383) and several 5-HT antagonists inhibit spontaneous ovulation (457).

Actually, the hormonal environment of the animal appears to be critical to the expression of 5-HT actions on gonadotropin secretion and ovulation. Indeed, 5-HT system can be modulated by gonadal steroids (222,515,598) and in several mammalian species, 5-HT receptors are colocalized with estrogen receptors beta (250), indicating that 5-HT and reproductive endocrine signaling pathways are closely associated. Accordingly, differential effects are observed in male and female rats: neonatal exposure to androgen is responsible for the sex difference in the LH response to 5-HTP, a 5-HT precursor, a difference which may be associated with a regulatory action of 5-HT on the cyclic hypothalamic control of gonadotropin secretion (501). 5-HTP has been shown to stimulate FSH release in normal rats and to inhibit it in castrated rats, testosterone concentration being a relevant factor in determining the 'type' of effect produced (331).

The functional interactions between 5-HT and reproductive functions have also been demonstrated in other vertebrates: b-In other vertebrates

In birds, 5-HT synthesized in the hypothalamus exerts an inhibitory influence on reproduction: elevation of 5-HT levels directly inhibits GnRH synthesis and LH secretion in female turkey (256) or hen (657) and male domestic fowl (257). Conversely, blockade of the serotonergic system generally stimulates gonadotropin secretion and enhances gonadal development, as shown in young female turkeys (256), or in aging male roosters [START_REF] Avital-Cohen | Role of the serotonergic axis in the reproductive failure associated with aging broiler breeder roosters[END_REF].

In teleosts, by contrast to what is observed in birds, hypothalamic 5-HT neurons exert a positive stimulatory influence on reproductive neuroendocrine function and gonadotropin secretion (for review (621)). Specifically, 5-HT stimulates GnRH release, LH release and socio-sexual behaviors, acting at different levels. At the hypothalamic level, a close association of 5-HT fibers with GnRH neurons has been observed in the Atlantic croaker (354). However, central administration of 5-HT has no effect on preoptic GnRH1 mRNA levels (782), indicating that 5-HT may stimulate GnRH release but not synthesis. As a matter of fact, 5-HT stimulates GnRH release from the hypothalamus of the goldfish and seabream (696, 902). In the zebrafish, 5-HT receptors are present in several regions containing GnRH neurons (539) suggesting possible expression of 5-HT receptors in GnRH neurons, as in mammals [START_REF] Bhattarai | Serotonin acts through 5-HT1 and 5-HT2 receptors to exert biphasic actions on GnRH neuron excitability in the mouse[END_REF].

At the pituitary level, in several teleost species, 5-HT stimulates gonadotropin release in vivo and in vitro (goldfish (730,731,878); Atlantic croacker (353,355)). In some other teleost species, 5-HT alone has no influence on spontaneous LH release, but potentiates GnRH analog-induced LH secretion when co-administered (Atlantic croacker (878); Prussian carp (729)). Interestingly, the stimulatory action of 5-HT on GnRH release is time-and seasondependent (355), and the mode of action of 5-HT on gonadotropin release also changes as a function of the reproductive stage: in the Atlantic croaker, the effect of 5-HT is more pronounced in mature than in sexually regressed fish (353).

Therefore, as in mammals, the stimulatory action of 5-HT on gonadotropin secretion in teleost appears to be modulated by various factors such as gonadal steroids, environmental conditions and social cues (for review (621)).

c-In other metazoans

Together with DA and NE, 5-HT represents a possible endocrine and neuronal link between endogenous and exogenous signals allowing non-vertebrates to modulate reproductive functions in conjunction with environmental constraints (368). In non-vertebrates, the function and location of 5-HT have been studied mainly in arthropods, mollusks and annelids.

In crustaceans, 5-HT is involved in various physiological processes including sexual behavior and reproduction (191,666,668,669,711). Specifically, 5-HT stimulates release of gonad stimulating hormone (GSH) in the crayfish Procambatus clarkia (668) and in the fresh water crab (620) and also accelerates testicular maturation in the fiddler crab (666, 667) and the red swamp crayfish (668) as well as ovarian maturation and spawning in the white shrimp (827).

In several species of mollusks, 5-HT and its receptors play an important role in reproduction, through stimulation of biosynthesis and release of active egg-laying peptide precursor proteins, i.e. control and initiation of gamete release, and gamete maturation. For instance, studies on bivalves show that 5-HT levels change during the different stages of the sexual cycle (resting, developing, maturing and egg-laying) in the gonads and cerebroid ganglia of mussels, and that the endocrine function of gonads in marine bivalves is regulated through monoamine neurosecretions arising from the cerebroid ganglia (368). Moreover, administration of 5-HT induces oocyte maturation and spawning (282,466,766). The endogenous 5-HT signal is transmitted to the oocyte through 5-HT receptors [START_REF] Bandivdekar | Demonstration of serotonin receptors in isolated spisula oocyte membrane[END_REF]857).

In annelids such as Nereidae, immunopositive staining for 5-HT is observed in neurons of the brain of Nereis diversicolor (278) and 5-HT exerts a positive effect on oocyte development, probably by stimulating a gonadotrophic hormone, present in mature females (392).

Altogether these studies indicate a conserved or convergent role of 5-HT in the control of reproduction in various bilateria, protostomes and deuterostomes (Figure 12). The presence of 5-HT receptors has been demonstrated in cnidarian, thus before the emergence of bilateria (for review (860)), but to our knowledge the effect of 5-HT on reproduction in this phylum

has not yet been addressed.

Histamine (HA)

The possible stimulatory effect of histamine (HA) on LH secretion was first evidenced in the rabbit by Sawyer (674) who reported that icv injection of HA induces ovulation and increases plasma LH levels in animals lightly anesthetized with pentobarbital but not awake or etheranesthetized. Subsequent studies, however, provided inconsistent results, likely depending on sex steroid environment: icv injection of HA increases plasma LH levels in proestrous or ovariectomized estrogen and progesterone-primed female rats (157,160,418), but has no effect in males (156,158). Actually, HA participates in the neuroendocrine regulation of pituitary hormone secretion by an indirect action at a hypothalamic level: In mammalian brain, HA cell bodies are located exclusively in the tuberomammillary nucleus (TMN) of the posterior hypothalamus (253) and send their axons all over the central nervous system. In the hypothalamus they arborize extensively and may thereby influence the release and function of various hypothalamic neuropeptides and hormones (254), including GnRH (368, 395):

GnRH-induced secretion of LH in female rats (497). By contrast, it does not affect LH release from isolated rat pituitary cells [START_REF] Bicknell | A quantitative assay for luteinizing hormone releasing hormone (LHRH) using dispersed pituitary cells[END_REF] or pituitary fragments (497).

Considering the ancient origin of HA, investigation on its potential role on reproductive function in other vertebrates and other metazoa would deserve to be launched.

GABA

GABA is an inhibitory neurotransmitter extremely abundant in the brain of all vertebrates, that plays a role in the control of reproduction in various vertebrate classes. a-In mammals, the influence of GABA on LH secretion has long been demonstrated [START_REF] Anderson | Effects of gamma-aminobutyric acid receptor agonists on the secretion of growth hormone, luteinizing hormone, adrenocorticotrophic hormone and thyroid-stimulating hormone from the rat pituitary gland in vitro[END_REF]159,388,560,839). The distribution of hypothalamic GABAergic neurons and their involvement in the neural control of reproductive processes are now well documented (451).

Although both GABA A and GABA B receptors have been identified in rat pituitary gonadotrope cells [START_REF] Anderson | Effects of gamma-aminobutyric acid receptor agonists on the secretion of growth hormone, luteinizing hormone, adrenocorticotrophic hormone and thyroid-stimulating hormone from the rat pituitary gland in vitro[END_REF] and that evidence exists for a possible direct stimulatory effect of GABA on the LH cells (842), the vast majority of studies support a key inhibitory role of GABA on gonadotropin release, predominantly at the central level, through modulation of the GnRH neuron activity and secretion. Notably, increasing endogenous GABA concentration by drugs, GABA or GABA agonist administration, in rats and non-human primates, prevents ovulation and pulsatile LH release, and blunts the LH surge induced by estrogen or an estrogen-progesterone combination (162). GABA infusion into the preoptic area or intraperitoneal injection of muscimol, a GABA A receptor agonist, blocks the LH surge [START_REF] Adler | Evidence for gamma-aminobutyric acid modulation of ovarian hormonal effects on luteinizing hormone secretion and hypothalamic catecholamine activity in the female rat[END_REF]277), while the GABA A receptor antagonist, bicuculline, advances the timing of the LH surge (363). Moreover, GABA release in the preoptic area decreases prior to and during the time of the LH surge (317).

GABAergic activity is known to be sensitive to environmental conditions (183) and the alteration of GABAergic neuronal activity is likely associated with the season-dependent reproductive cyclicity in seasonal mammals (235). GABAergic activity may also depend on the stage of reproductive development: in female mice, at puberty, the effect of GABA on GnRH neurons switches from depolarization to hyperpolarization ((259). Both autoradiographic and immunohistochemical studies show that a large proportion of GABA neurons in the diencephalon represents targets for estrogens (197,277,388,471), and it has been postulated that these neurons may mediate estrogen feedback on GnRH neurons, (388,752), as suggested by the existence of synaptic contacts between GABAergic terminals and GnRH neurons (405,733). Interestingly, it appeared recently that a subpopulation of GnRH neurons in the adult mouse forebrain is GABAergic and thus that GnRH neurons could secrete GABA to regulate their own activity (917).

GABA exerts its regulatory effects via two main receptors, the GABA A and GABA B subtypes. The origin and evolution of the GABA receptors is highly complex. As some publications exist, focusing on the phylogeny of the multiple GABA A receptor (458,650,803), this topic will not be adressed in the present review.

In vivo experiments undertaken in adult rats, sheep and monkeys all indicate that the inhibitory effect of GABA on LH secretion is mediated through the GABA A receptors located on the soma of GnRH neurons (276,277,495,683). Furthermore, GnRH neurons express functional GABA A receptors that may inhibit GnRH neuronal excitability (260,717,743).

Much less is known about the possible involvement of GABA B receptors. Functional GABA B receptors are present in various hypothalamic neurons [START_REF] Akema | The mode of GABAB receptor-mediated inhibition of the preovulatory luteinizing hormone surge in female rats[END_REF][START_REF] Akema | Modulation of pulsatile LH secretion by baclofen, a selective GABAB receptor agonist, in ovariectomized rats[END_REF]387,846) but studies examining their role suggest that major species differences exist. In the ewe, GABA B receptors mediate inhibition of GnRH secretion during the non-breeding season, but not during the breeding season, this change being possibly part of the mechanism for the seasonal shift in the negative-feedback effect of estradiol on LH secretion (683). In the adult rat, GABA B receptors play an important role in controlling the excitability of GnRH neurons especially in females (429). Interestingly, GABA stimulates GnRH secretion in the adult rat [START_REF] Bilger | A conditional tetracyclineregulated increase in Gamma amino butyric acid production near luteinizing hormonereleasing hormone nerve terminals disrupts estrous cyclicity in the rat[END_REF]161). Yet, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive (861).

b-In other vertebrates

In birds: The domestic turkey is a seasonally breeding bird with a reproductive cycle regulated by photoperiod and terminated by the state of photorefractoriness (720). In this bird, GABAergic neurotransmission in the hypothalamic premammillary nucleus regulates reproductive seasonality and the onset of photorefractoriness (374) through GABA A receptors (374).

In teleost fish, there is also good evidence for the involvement of GABA in the control of LH release (451,799,921). Following the discovery of a heavy GABAergic innervation of the anterior pituitary in goldfish, (334, 335), the effects of GABA have been explored, mainly in goldfish (for review (616)), and to a lesser extent in trout Oncorhynchus mykiss. By contrast to its inhibitory effect in mammals, GABA predominantly stimulates LH secretion in adult goldfish and trout, although inhibitory actions have been described in two other species, the Atlantic croacker (356) and the common carp (116).

In goldfish, intraperitoneal injection of GABA increases serum gonadotropin levels (338).

Injection of a GABA transaminase inhibitor, that augments GABA levels within the hypothalamus and pituitary, also induces an increase in serum gonadotropin levels (723). This stimulatory effect of GABA on gonadotropins can be accounted for by two major mechanisms: stimulation of GnRH secretion (338, 723) and inhibition of DA release (723, 797, 798) at the brain level. In vitro, GABA also induces a dose-related stimulation of GnRH release from pituitary slices, which in teleosts contain GnRH nerve terminals (797). By contrast, GABA does not directly stimulate LH release from dispersed goldfish pituitary cells in vitro (338). The in vivo stimulatory effect of GABA varies seasonally and is modulated by sex steroids (338,356,459,798). Both muscimol (a GABA A receptor agonist) and baclofen (a GABA B receptor agonist) stimulate LH secretion in females, indicating that both receptor subtypes may mediate the effect of GABA (459, 799).

In rainbow trout, GABA exerts an overall stimulatory effect on basal and GnRH-induced LH, but also on FSH secretion, both in vivo and in vitro, and these effects are also highly dependent on the sex and the reproductive stage of the fish (451). As in mammals and goldfish, a role for GABAergic neurons as target cells for oestrogen feedback on LH release has been hypothesized in rainbow trout because oestrogen receptors are present in GABAergic, but not in GnRH neurons. In addition, the stimulatory action of GABA may also be exerted directly onto the gonadotrope cells of the pituitary, as GABA stimulates basal and GnRH-induced FSH and LH secretion from dispersed pituitary cells (451).

In the zebrafish brain, the connection between GABAergic and GnRH neurons has been recently evidenced: GnRH3 neurons are directly contacted by GABAergic neurons in the ventral telencephalon and hypothalamus (733). Moreover, as shown also in mouse (917), some GnRH neurons in the anterior part of the telencephalon coexpress GAD67, thus being also GABAergic. Administration of GABA B receptor agonists and antagonists support the implication of GABA B receptors in the regulation of GnRH neurons (733).

In agnaths, studies in sea lamprey also indicate that GABA may directly affect GnRH release in the brain: dual-label in situ hybridization shows that GABA cells are closely apposed to GnRH cells in the rostral hypothalamus and preoptic region (647). In vitro perfusion or in vivo injection of GABA and its analogs both significantly increase GnRH in the brain (647), suggesting that GABAergic control of GnRH is phylogenetically ancient. c-In other metazoa GABA may also play some role in the control of reproduction in other metazoa: for instance, GABA induces spawning in non-chordate deuterostomes, echinoderms (764). GABA also enhances reproduction in protostomes such as rotifers (220), indicating a role of GABA in the control of reproduction in both deuterostomes and protostomes. The presence of GABA receptors demonstrated in cnidaria, attests the early origin of GABA receptors before the emergence of bilateria (for review (346)), and should inspire future investigation on the possible role of GABA in reproduction of basal metazoa (Figure 12). 223), and the substances known as neurotransmitters appeared long before the development of the most primitive nervous system and even multicellular organisms ( 79): Organisms like protists and animals devoid of nervous system, as sponges and placozoans, produce a wide array of molecules, which are in some cases identical to the corresponding compounds found in higher taxa (223). Monoamines (catecholamines, indoleamines and HA) are found in many protozoans and in almost all metazoans (811). Non-bilaterian metazoans, with or without neurons, exhibit many components of the molecular toolkits for synapse function. GABA, catecholamines, and indoleamines as well as a large number of G protein-coupled receptors for monoamines, and biogenic amine-synthesizing enzymes can be found in prebilaterian animals such as cnidarians [START_REF] Bosch | Back to the Basics: Cnidarians Start to Fire[END_REF]. GABA is used as a signal molecule by non nervous cells of vertebrates (224) and also in sponges (173) and in plants [START_REF] Bouché | GABA signaling: a conserved and ubiquitous mechanism[END_REF].

The catecholaminergic signalling has an old phylogenetic history and the enzymatic pathway for the biosynthesis and degradation of monoamine transmitters and the β-adrenergicmediated mechanisms were conserved throughout evolution from early metazoans to Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019. mammals (223). Alpha-adrenergic receptors are found in representatives of two major clades of bilateria, the protostomes and the deuterostomes [START_REF] Bauknecht | Ancient coexistence of norepinephrine, tyramine, and octopamine signaling in bilaterians[END_REF]. If we take the example of monoamines, according to Turlejski hypothesis (811): their "earliest role has been as intracellular regulators of cell activity". Produced either inside the cell or entering it from its environment, they act directly on some of the intracellular signaling systems, and "cause long-lasting changes in the cell functional state, that allow the organism to adapt to its environment". "However, very early in evolution, they acquired functions of hormones", i.e. molecules of external origin acting on specific receptors localized in the cell membrane and stimulating specific intracellular second messengers to cause long-term changes in the functional state of cells. "Later on in evolution, biogenic amines acquired functions of neuromodulators", thus produced and released by specific neurons, and able to modulate the activity of other neurons, through specific receptors placed within synaptic explain why they have been selected for paracrine communication and then for nervous communication (263). 6.4.2. Non-peptidic neuromediators as potential targets for neuroendocrine disruption of reproduction: a phylogenetic approach Neuroendocrine disruptors (NEDs) are defined as "pollutants in the environment that are capable of acting as agonists/antagonists-or altering the synthesis and/or metabolism-of neuropeptides, neurotransmitters or neurohormones, which subsequently alter diverse physiological, behavioral or hormonal processes to affect an animal's capacity to reproduce, develop and grow, or deal with stress and other challenges" (863).

While NEDs are now well known to adversely affect reproduction through binding to steroid receptors (mimicking or antagonizing the activity of steroid hormones), it is important to mention that they may also affect reproductive functions by acting upon neurotransmitter systems (such as DA, GABA, NE and 5-HT) that modulate GnRH output (150, 400). To take only a few examples in mammals: (1) bisphenol A (BPA): When pregnant rats are orally administered BPA, the turnover of DA and 5-HT in the forebrain are accelerated in both the mother and the offspring, suggesting an increase in the release of both monoamines from nerve endings (288). BPA exposure, at even lower doses than environmentally relevant levels, was shown to have a great impact on monoamine levels in neonatal rat brain over 28 d after its disappearance (463). In male mice, an increase in anxiety-like behavior induced by perinatal exposure to BPA seems to be related to decreases in DA metabolites and in the activity of monoamine oxidase (MAO)-B in the brain. ( 462). ( 2) Polychlorinated biphenyls (PCBs), that are industrial chemical products, also affect DA and 5-HT levels in the brain: they have been shown to bind to DA,and NE receptors (689).Decreased brain levels of DA, DOPAC and HVA are observed in the brain of pregnant rats treated with PCBs, but also Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on [START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF] in the brain of their offspring (289). PCBs and brominated flame retardants (BFRs) decrease DA turnover, primarily via inhibition of DA transporters DAT and VMAT, and also decrease the uptake of glutamate and GABA, inhibiting GABA signaling, and decreasing 5-HT levels.

Several epidemiological studies have shown that PCBs and BFRs may be responsible for similar effects in humans (for review (200)). ( 3) GABAergic neurons in the preoptic area of the rat brain are known targets of TCDD, a dioxin, and may mediate developmental effects of this contaminant on reproductive function (270).

In birds also, several hypothalamic neural systems proved to be responsive to NEDs (571-573): for instance, there is evidence in the quail that the catecholamine and indoleamine systems may be altered by perinatal exposure to NEDs (571).

In fish (for review (863)) various pollutants have been shown to impact neurotransmitters involved in the neuroendocrine control of reproduction. For example, (a) the antidepressant fluoxetine (FLU), one of the most prevalent environmental pharmaceutical contaminant in North American and European aquatic ecosystems, that is a selective 5-HT reuptake inhibitor (SSRI), was reported to affect multiple neuroendocrine pathways and behavioral circuits in teleost fishes including disruptive effects on reproduction (481). Recently, in zebrafish embryos, in very much the same as in mammals, FLU was shown to impair the serotonergic, mill effluents contain compounds that interact with key enzymes and receptors that regulate the GABAergic, glutamatergic and dopaminergic modulation of GnRH and LH, thereby impairing reproduction in the goldfish [START_REF] Basu | Pulp and paper mill effluents contain neuroactive substances that potentially disrupt neuroendocrine control of fish reproduction[END_REF]. (e) Bifenthrin (BF), a pyrethroid insecticide, alters dopaminergic function in zebrafish embryos and juveniles [START_REF] Bertotto | Effects of bifenthrin exposure on the estrogenic and dopaminergic pathways in zebrafish embryos and juveniles[END_REF].

While most investigations on NEDs are carried out with vertebrate models, research on non vertebrate species led to similar results: For instance, (i) in insects, azadirachtin (AZA), an insecticidal limonoid with antifeeding and sterilizing properties, blocks neurosecretion from the corpus cardiaca, interacting with the cholinergic, GABAergic and 5-HT systems (504). (ii)

In crustaceans, cadmium and mercury have inhibitory effects on ovarian maturation in the red swamp crayfish, partly by inhibiting 5-HT-stimulated gonad-stimulating hormone release, and preventing the ovaries from responding to this hormone (633). Antidepressants, by interfering The neuroendocrine systems, as the links between the brain and peripheral endocrine systems, play key roles in the ability of an organism to respond to its environment. They are thus highly vulnerable to disruption by environmental contaminants such as industrial chemicals, pesticides, pharmaceuticals…, the worldwide presence of which is now demonstrated. NEDs are known to exert some of their adverse effects acting directly upon neurotransmitter pathways that regulate the neuroendocrine systems.

As most neurotransmitter molecules, as well as some of their receptors and transporters are phylogenetically ancient and conserved within the animal phyla, NEDs may interact with them and affect the neurotransmission systems of all metazoan. Chemical disruption of neuromediator signaling may therefore adversely affect health and reproduction in human but also in a diversity of wildlife thus encompassing the whole ecosystem.

In conclusion, molecular families of neuromediators, hormones, their biosynthesis enzymes and their receptors, involved in the neuroendocrine control of vertebrate reproduction, have an ancient origin in metazoa, pre-existing the emergence of vertebrates and the innovation of the brain-pituitary axis (Figure 13). Evolutionary scenarios, based on phylogeny approaches, enable retracing the origin and evolution of these molecular families, highlighting the impacts of gene and genome duplications, as well as gene loss events. Combined with physiological data they allow inferring evolutionary constraints and mechanisms leading to functional conservation and diversification of the actors of the neuroendocrine control of reproduction.

Call Out Box

•

Reproduction is the essential biological process of living organisms and is therefore submitted to strong evolutionary constraints.

•

In human as in other vertebrates, reproduction is controlled by the brain-pituitary gonadotropic (BPG) axis. Evolutionary endocrinology contributes to a better understanding of the neuro-endocrine control of reproduction in living organisms including human, by providing new insights on the origin, conservation and variations of the key actors of the BPG axis.

• As revealed by molecular phylogeny analyses, many actors that have been recruited

for the BPG axis in vertebrates (neuromediators, neurohormones, hormones, biosynthesis enzymes, and receptors) belong to large molecular families of an ancient origin in metazoa.

•

The number of actors of the BPG axis has expanded via the two rounds of whole genome duplication that occurred at the basis of the vertebrate lineage, which is at the origin for instance of the two gonadotropins LH and FSH and their sister hormone the thyrotropin TSH. Local gene duplications have also contributed to an increase of actor numbers, and such is the origin of human chorionic gonadotropin.

• An additional round of whole genome duplication has occurred at the basis of the teleost fish lineage, so that some "fish models" currently used for biomedical research, such as zebrafish or medaka, may present a larger number of actors as compared to human.

• Conversely to gene increase via duplications, gene loss events have also marked the evolutionary history of some BPG actor families, as is the case for kisspeptin receptors, with a single gene left in human, as compared to four in basal vertebrate representatives.

•

The synthesis and function of the BPG axis actors (neuromediators, neurohormones and hormones) are the targets of disruption by environmental pollutants from industrial, agricultural and pharmaceutical activities. The ancient origin of the BPG actor families makes a variety of living organisms both targets and sentinels of neuro-endocrine disruption.

This highlights some of the strong links between ecosystems, biodiversity health and human health, within the framework of the "OneHealth" concept.

1 .

 1 Discovery of pituitary gonadotropinsA role of pituitary gland activity on the development of gonads was suggested as far back as 1910 (132) by studies showing that hypophysectomy leads to an atrophy of genital organs.

  the α subunit of the Elephant shark (Callorhinchus milii -NCBI NM001292594.1) where C9 is replaced by an arginine, of the Tiger salamander (Ambystoma tigrinum -CN048018.1) with C6 also replaced by an arginine, and the Arabian camel (Camelus dromedarius -XM010987723.1) (but not C. bactarianus -XM_006178591.1 and C. ferus -XM_010948966.1) with C2 replaced by an aspartic acid. Whether these substitutions correspond to sequencing errors or to true mutations remains to be clarified. Two glycosylation sites are overall conserved except in crows (Corvus cornix -XM010404527.2, C. brachyrhynchos -XM_08640241.2 and C. macrorhynchos -AB563175.1) where the asparagine at the junction of loop 2 with the β3 strand is replaced by an aspartic. Carbohydrate side chains are predicted to impact on synthesis and storage, on receptor Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

Following

  up a previous work (360), Sedifeh et al. (2014) (690) examined the conserved synteny of chromosomes harboring GnRHR genes. They identified three pairs of GnRH-R subtypes in three paralogous linkage groups, suggesting that an ancestral pair emerged through local duplication before 2R. According to their model, 2R thus led to the generation of 6 subtypes of GnRH-R in the vertebrate ancestor. However, this model is based on a phylogenetic analysis whose conclusions have been recently strongly challenged (644, 873).

  ): the farp-1 gene (601, 841) encodes two peptides, neuropeptide FF (NPFF) and neuropeptide AF (NPAF) (896); the farp-2 gene (280) encodes prolactin-releasing peptide (PrRP) (280); the farp-3 gene (281, 426) encodes two peptides, RFRP-1 and RFRP-3 also referred to as neuropeptide VF (NPVF) or GnIH (281); the farp-4 gene (227) corresponds to the Kiss-1 gene encoding kisspeptin (or metastin) peptides (375, 549); the farp-5 gene (104, 213, 322) encodes 26RFa, also named P518 or QRFP

  ); European starling: (814); zebrafinch: (788)). Moreover, GnIH receptor mRNA is expressed in different parts of the brain in quail and starling as shown by PCR (51), and more specifically in both GnRH-I and GnRH-II neurons in European starling Sturnus vulgaris as shown by ISH/ICC (814).

5. 2 . 4 .

 24 Current studies on the presence and role of GnIH in the reproduction in other vertebrates a. In other sauropsids In sauropsids, apart from birds, three GnIH peptides (GnIH, GnIH-RP-1 and GnRH-RP-2) have been characterized in the red-eared slider turtle Trachemys scripta elegans (821), in the Chinese softshell turtle and in the anole lizard (for reviews: (566, 807)), and they all possess the common C-terminal LPXRFamide motif, like the avian and mammalian peptides. However, few studies have investigated their potential physiological roles. Brain localization of GnIH by ISH and/or immunohistochemistry has been reported in the Japanese grass lizard Takidromus tachydromoides (350) and the red-eared slider turtle (821). In the lizard Calotes versicolor, ovarian localization of GnIH has also been reported and GnIH is able to suppress ovarian GnRH receptor expression (718). b-In amphibians: a GH-releasing factor (for review: (315))

  Kiss in the control of reproduction in mammals a-Stimulation of GnRH neurons Peripheral (subcutaneous, sc) or intracerebroventricular (icv) injection of kisspeptin increases plasma levels of gonadotropins and this response is abolished by the use of a GnRH antagonist (icv, mice: (237); icv, rats: (307); sc, rats: (464); icv, monkeys: (698)), suggesting a stimulatory effect of kisspeptin on gonadotropins via activation of hypothalamic GnRH Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

(

  535); male chub mackerel gnrh1: (546, 691, 692)), stimulatory (grouper gnrh1: (707)) or inhibitory (striped bass gnrh1, 2 and 3: (918)) effects of Kiss peptides on brain transcript levels of gnrh. Depending on the administration routes, in the female chub mackerel, both stimulatory (sc (692)) and inhibitory (icv (546)) effects of Kiss2 have been reported on brain gnrh1 mRNA levels. These in vitro and in vivo studies thus indicate variable effects of kisspeptins on GnRH in teleosts.

  Data in non-mammalian vertebrates indicate that PrRP and C-RFa/PrRP2 are able to stimulate PRL release in vitro (teleosts: C-RFa in tilapia, (685); C-RFa in rainbow trout, (508, 646)) and in vivo (bird: comparaison C-RFa et mPrRP, (763); amphibian: PrRP, (655); teleost:

6. 1 . 2 .

 12 Non-peptidic neuromediators produced via enzymatic synthesis: phylogeny of enzymes to retrace their evolutionary history Nonpeptidic neuromediators are decarboxylated derivatives of amino acids: DA and NE are synthesized from tyrosine, 5-HT from tryptophan, HA from histidine, and GABA from glutamic acid, in one or more enzymatically catalysed reactions of which the first serves as the rate-limiting step. a -Aromatic Amino acid hydroxylases (AAAH)

  ]. D1 and D2 receptors both belong to the group A (rhodopsin-like) of the GPCR superfamily but have different structural features. D1 receptor genes are intronless, and D1 receptor proteins exhibit a short third cytoplasmic loop and a long C-terminal tail. They are coupled to the Gs family of G proteins, and D1 receptor agonists promote adenylyl cyclase activity. In contrast, D2 receptor genes contain several introns and encode a long third cytoplasmic loop and a short Cterminal tail. D2 receptors are coupled to the Gi/Go family of G proteins, and D2 receptor agonists inhibit adenylyl cyclase activity. Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

6. 2 . 3 .

 23 Evolution of Dopamine D2 receptors The D2 receptors have been diversified as a consequence of genome duplications in early vertebrates. In mammals, three DA receptors (D2, D3 and D4) are classified as the D2 class. The classification and nomenclature of DA receptors has been initially based on the set of receptors found in eutherian mammals. When more DA receptors have been found in other groups of vertebrates, the necessity of revisiting DA receptor classification was raised by some authors (147, 891, 892). a-Impact of WGD

  c-In other metazoaFew data are available on the role of NE in the reproductive function in other metazoa. In mollusks, cyclic variations of NE strongly support its participation in the reproductive cycle of bivalve species. Notably, marked variations in NE content occur in the gonads and pedal ganglia of mussels, with a 3 to 4-fold increase during gametogenesis and a decline during spawning (368). Similarly, increased NE levels are measured in gonad of the female Pacific lion's paw Scallop during gametogenesis stages (developing and maturing stages) while NE concentrations drop after spawning, suggesting that NE exerts a direct control over gametogenesis (433).

6. 4 .

 4 Neuromediators and reproduction: from conservation to disruption 6.4.1. Ancient origin of neuromediators and receptors in metazoan The neurotransmitter function of DA, NE, 5-HT, HA and GABA in adult organisms is their more recently developed function. Cell communication through secreted, diffusible signals is phylogenetically older than neural transmission (

  contacts. "Finally, preserving some of the evolutionary older functions, monoamines took the function of neurotransmitters conveying fast changes", through receptors activating ion channels (811). The development of a signaling system requires the evolution of a mechanism for producing signals, receptors and adaptive reactions to the signal. Various data now support the evolutionary model proposed by Harris and Zahavi (263) to explain the selection of these precise molecules for intercellular communication: « Classical neurotransmitters » are small molecules that are catabolitic products of biological molecules invoved in basal cell metabolism: DA and NE are produced from tyrosine, 5-HT from tryptophan, HA from histidine, GABA from glutamate,… and the extracellular release of these molecules reflects the metabolic activity of the secretory cell. Their (i) physico-chemical characteristics, which are best suited to display reliably the levels of specific metabolic activities, and (ii) toxicity which induced the selection by neighboring cells of membrane proteins to bind them, may Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

  dopaminergic and adrenergic neurotransmission systems at environmentally relevant concentrations, by down-regulating transcription patterns of monoamine receptors and transporters (134). (b) PCBs disrupt the stimulatory 5-HT/GnRH pathway controlling LH secretion activity by inhibiting hypothalamic TPH and decreasing 5-HT availability in croakers (357). (c) Mercury, both in its inorganic and organic forms, is capable of impairing the monoaminergic neurotransmitters involved in the regulation of GnRH and gonadotropins: after mercury exposure, 5-HT concentrations are decreased in the brains of several fish species, whereas levels of NE and DA are increased (for review (133)). (d) Pulp and paper Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

with 5 -

 5 HT, DA or NE neurotransmission, affect freshwater amphipod activity patterns, marine amphipod photo-and geotactic behavior, and daphnid reproduction and development (for review (198)). (iii) In mollusks, in the freshwater mussel, exposure to estrogenic chemicals present in municipal effluents alters the normal metabolism of 5-HT and DA, both of which are involved in sexual differentiation (217). Antidepressants affect spawning and larval release in bivalves and reduce fecundity in snails. Exposure to the environmental contaminant, serotonergic antidepressant fluoxetine, induces spawning in estuarine and freshwater bivalves (for review (198)). 6.4.3. The "One Health concept"

Zohar Y .

 . Differential and Gonad Stage-Dependent Roles of Kisspeptin1 and Kisspeptin2 in Reproduction in the Modern Teleosts, Morone Species1. the Teleost, Morone saxatilis1. Biol Reprod 93: 1-12, 2015. 921. Zohar Y, Muñoz-Cueto J, Elizur A, Kah O. Neuroendocrinology of reproduction in teleost fish. Gen Comp Endocrinol 165: 438-455, 2010.

Figure 1 .

 1 Figure 1. Neuroendocrine control of reproduction in mammals: the brain-pituitarygonad axis. Internal and environmental factors are integrated at the brain level and modulate the activity of gonadotropin-releasing hormone (GnRH) neurons. GnRH is released in the hypophyseal portal vessel system and controls the production of pituitary gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), which in turn control gonad activity. A variety of neuromediators, peptidic and non-peptidic, are also involved in the control of GnRH and gonadotropins, such as Kisspeptin (Kiss), gonadotropin-inhibiting hormone (GnIH), dopamine (DA), norepinephrine (NE), serotonin (or 5-hydroxytryptamine 5-HT), Histamine (HA), gamma-aminobutyric acid (GABA). The pituitary gland, as a relay between brain neurons and peripheral glands is considered as a vertebrate innovation.

Figure 2 .

 2 Figure 2. Vertebrate phylogeny with a special focus on whole genome duplications. Two rounds (1R and 2R) of whole genome duplication (WGD) occurred at the basis of the vertebrate lineage. Whether the 2nd round occurred before or after (doted line) the emergence

Figure 3 .

 3 Figure 3. Metazoan phylogeny.Human belong to the vertebrate, chordate, deuterostome, bilateria lineages. Urochordates are considered as the sister clade of vertebrates. Among bilateria, protostomes are the sister clade of deuterostomes. The most consensual classifications of protostomes distinguish two sister clades, lophotrochozoa and ecdysozoa. Cnidaria represent one of the basic groups of metazoa.

Figure 4 .

 4 Figure 4. Schematic representation of the glycoprotein hormone (GpH) α and β subunits and comparison with predicted GPA2 and GPB5 structures. Amino acids are represented by circles. Glycosylation chains are represented by Y shape sign. Position of intron splicing sites is indicated by V shape sign. The disulfide bonds are symbolized by bars, red bars between red circles for those responsible for the cystine-knot structure and in grey for the additional ones. The conserved cysteine residues are numbered. Location of the β strands (β1-β4) and loops (L1-L3) is indicated.

Figure 5 .

 5 Figure 5. Schematic representation of the gene duplication, genome duplication and gene loss events leading to the extant repertoire of glycoprotein hormone subunit related genes in vertebrates. 1R, 2R: first and second rounds of whole genome duplication in early vertebrates; 3R: third round of whole genome duplication in early teleosts. 1* The GPA2-GPB5(a) tandem was

Figure 6 .

 6 Figure 6. Evolutionary scenario of the GnRH family in vertebrates (adapted from (219)). Anc GnRH: ancestral gonadotropin-releasing hormone gene. 1R, 2R: first and second rounds of whole genome duplication in early vertebrates; 3R: third round of whole genome duplication in early teleosts. Black cross: gene loss. Red arrow: local gene duplication.

Figure 7 .

 7 Figure 7. Evolutionary scenario of the GnRH receptor family in vertebrates (adapted from (644)). Anc GnRHR: ancestral gonadotropin-releasing hormone receptor gene. 1R, 2R: first and second rounds of whole genome duplication in early vertebrates; 3R: third round of whole genome duplication in early teleosts. Black cross: gene loss. Red arrow: local gene duplication.

Figure 8 .

 8 Figure 8. Two evolutionary scenarios of the GnRH-like systems in bilaterians (adapted from (654)). Anc: ancestral; GnRH: Gonadotropin-releasing hormone; CRZ: corazonin. AKH: adipokinetic hormone; ACP: AKH/corazonin-related peptide. Black cross: gene loss. Red arrow: local gene duplication.

Figure 9 .

 9 Figure 9. Evolutionary relationships between RF-amide and non RF-amide peptide families. RF-amide peptides are encoded by 5 distinct genes in mammals, which have been named by Dockray (153) farp-1 to 5, based on the chronology of their discoveries. Various nomenclatures are used according to authors and phyla such as: Neuropeptide F (NPFF) or PQRF for farp-1; Prolactin-releasing peptide (PrRP) for farp-2; Gonadotropin-inhibiting hormone (GnIH) or Neuropeptide VF (NPVF) or LPXFR for farp-3; Kiss for farp-4; QRFP or 26RF for farp-5. The figure displays some current hypotheses on their evolutionary relationships (for reviews: (359, 567, 807, 904)): NPFF (farp-1) and GnIH (farp-3) would be the closest related RF-amide peptide families, likely having a common PQRF ancestor and resulting from one of the two rounds of whole genome duplication (1R/2R WGD) that occurred in early vertebrates. QRFP (farp-5) would be related to NPFF (farp-1) and GnIH (farp-3) families via a local gene duplication of their common ancestor, before the WGD duplication of NPFF and GnIH. PrRP (farp-2) and Kiss (farp-4) would be more related to non RF-amide peptide families than to the other RF-amide peptide families: PrRP to neuropeptide Y (NPY) and QRFP to galanin and spexin, via local gene duplications, respectively.

Figure 10 .

 10 Figure 10. Evolutionary scenario of the Kiss family in vertebrates (adapted from (587)). Anc Kiss: ancestral Kisseptin gene. 1R, 2R: first and second rounds of whole genome duplication in early vertebrates; 3R: third round of whole genome duplication in early teleosts. Black cross: gene loss.

Figure 11 .

 11 Figure 11. Evolutionary scenario of the Kiss receptor family in vertebrates (adapted from (587)). Anc KissR: ancestral Kisseptin receptor gene. 1R, 2R: first and second rounds of whole genome duplication in early vertebrates; 3R: third round of whole genome duplication in early teleosts. Black cross: gene loss.

Figure 12 .

 12 Figure 12. Ancient origin of neuromediators involved in the neuroendocrine control of reproduction.Various neuromediators such as Dopamine (DA), norepinephrine (NE), serotonine (or 5hydrotryptamine, 5-HT), histamine (HA), gamma-aminobutyric acid (GABA) are involved in the brain control of reproduction in mammals. Their presence in other vertebrates, in other deuterostomes, in protosomes and in cnidaria (non-bilateria), suggests an ancient origin in metazoa. They may also have exerted an early role in reproduction in metazoa. Straight letters: neuromediator with a reported role in the control of reproduction. Italic letters with question mark: neuromediator present but no information on its putative role in reproduction.

Figure 13 .

 13 Figure 13. Schematic drawing of the origin of some major actors of the brain-pituitary control of mammalian reproduction. The pituitary gland is a vertebrate innovation ensuring the relay between the brain and peripheral glands and target organs. Molecular families of the various actors of the vertebrate brain-pituitary reproductive neuroendocrine axis have an ancient origin, largely preceding the emergence of the vertebrate lineage. Local and whole genome duplications in vertebrates contributed to the diversification of the Kiss and GnRH (Gonadotropin-releasing hormone) systems and of the glycoprotein (GP) homones, pituitary gonadotropins FSH and LH, and chorionic gonadotropin CG. 1R, 2R: first and second rounds of whole genome duplication in

  .physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019. .physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019. from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

  .physiology.org/journal/physrev at Univ ofMassachusetts (128.119.168.112) on[START_REF] Fontaine | Spécificités des glycoprotéines hypophysaires à activité thyréotrope et Downloaded from www[END_REF]

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Table legends Table 1 . Sequences of GnRH-like peptides

 legends1

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Proceedings Biol Sci 274: 2693-2701, 2007. Downloaded from www.physiology.org/journal/physrev at Univ of Massachusetts (128.119.168.112) on October 20, 2019.

Acknowledgements. The authors thank Dr Anne Gaëlle Lafont for her contribution to figure drawings.

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Gen Comp Endocrinol 159: 158-169, 2008. 719. Singh P, Krishna A, Tsutsui K. Effects of gonadotropin-inhibitory hormone on folliculogenesis and steroidogenesis of cyclic mice. Fertil Steril 95: 1397Steril 95: -1404Steril 95: , 2011. 720. 720. Siopes TD. Temporal characteristics and incidence of photorefractoriness in turkey hens. Poult Sci 80: 95-100, 2001.

GnRH1 GnRH2 GnRH3

GnRH1 GnRH2 GnRH3