Isabelle Néant

Jacques Haiech

Marie-Claude Kilhoffer

Francisco J Aulestia

Marc Moreau

Catherine Leclerc
email: catherine.leclerc@univ-tlse3.fr

Ana Cristina Calvo

Marisa Brini

Ca 2+ -Dependent Transcriptional Repressors KCNIP and Regulation of Prognosis Genes in Glioblastoma

Keywords: Ca 2+ signaling, neuronal Ca 2+ sensors, KCNIP, glioblastoma multiform, cancer stem cells (CSC), quiescence

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INTRODUCTION

Among tumors of the central nervous system, glioblastomas (GBMs) are the most aggressive and lethal primary astrocytic tumors in adults, with very poor prognosis [START_REF] Louis | The 2016 world health organization classification of tumors of the central nervous system: a summary[END_REF][START_REF] Lapointe | Primary brain tumours in adults[END_REF]. More than 90% of the patients show recurrence after therapies combining surgical resection, radiotherapy, and temozolomide (TMZ)-based chemotherapy, and the mean survival period rarely exceeds 2 years [START_REF] Stupp | Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[END_REF]. According to the cancer stem cell model, recurrence in GBM is attributed to a small sub-population of tumor cells called glioblastoma stem-like cells (GSLCs). These GSLCs have stemlike properties and are responsible for the initiation and the growth of the tumors [START_REF] Visvader | Cancer stem cells in solid tumours: accumulating evidence and unresolved questions[END_REF]. Indeed, the GSLCs provide all the subtypes of cells that comprise the tumor including some pseudo-endothelial cells [START_REF] Ricci-Vitiani | Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells[END_REF]. GSLCs are characterized by a molecular signature which combines markers of neural and/or embryonic stem cells and of mesenchymal cells. Numerous studies support the proposal that the behavior of the tumor, including proliferation, progression, invasion, and significant resistance to therapies, is determined by the self-renewing properties of the GSLCs [START_REF] Stupp | Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[END_REF][START_REF] Bao | Glioma stem cells promote radioresistance by preferential activation of the DNA damage response[END_REF][START_REF] Hegi | Brain tumors: molecular biology and targeted therapies[END_REF][START_REF] Stupp | Targeting brain-tumor stem cells[END_REF][START_REF] Murat | Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma[END_REF]. More importantly, this high resistance capacity to TMZ treatment have been attributed to slow cycling or relatively quiescent GSLCs [START_REF] Pistollato | Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma[END_REF][START_REF] Deleyrolle | Evidence for label-retaining tumour-initiating cells in human glioblastoma[END_REF]. Quiescent GSLCs have been identified in vivo in a mouse model of GBM [START_REF] Chen | A restricted cell population propagates glioblastoma growth after chemotherapy[END_REF] and in human GBM tumors [START_REF] Ishii | Histological characterization of the tumorigenic "peri-necrotic niche" harboring quiescent stem-like tumor cells in glioblastoma[END_REF]. Thus, targeting GSLCs and their stem cell-like properties may constitute one of the possible therapeutic challenges to significantly improve anti-cancer treatment regimens for GBM.

Ca 2+ is a crucial second messenger [START_REF] Carafoli | Why calcium? How calcium became the best communicator[END_REF] that controls a wide variety of cell functions from cell proliferation and apoptosis to organogenesis [START_REF] Berridge | The versatility and universality of calcium signalling[END_REF][START_REF] Machaca | Ca2+ signaling, genes and the cell cycle[END_REF][START_REF] Moreau | Ca2+ coding and decoding strategies for the specification of neural and renal precursor cells during development[END_REF]. Thus, the intracellular Ca 2+ concentration ([Ca 2+ ]i) is tightly regulated and involves Ca 2+ channels, pumps, and exchangers both at the plasma membrane and at the membrane of endoplasmic reticulum, mitochondria, or Golgi apparatus [START_REF] Bootman | Calcium Signaling[END_REF][START_REF] Humeau | Calcium signaling and cell cycle: progression or death[END_REF]. In addition, changes in [Ca 2+ ]i do not proceed in a stereotypical manner. The Ca 2+ signal can be described by its amplitude (variations of [Ca 2+ ]i levels) and by its spatial (sources of Ca 2+ ; organelles where changes occur) and timedependent (duration, frequency) components [START_REF] Berridge | Spatiotemporal aspects of calcium signalling[END_REF][START_REF] Haiech | Revisiting intracellular calcium signaling semantics[END_REF][START_REF] Smedler | Frequency decoding of calcium oscillations[END_REF][START_REF] Monteith | The calcium-cancer signalling nexus[END_REF]. The remodeling of Ca 2+ signaling contributes also to cancer hallmarks such as excessive proliferation, survival, or resistance to cell death [START_REF] Roderick | Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival[END_REF][START_REF] Prevarskaya | Remodelling of Ca2+ transport in cancer: how it contributes to cancer hallmarks?[END_REF] and accumulating evidence suggests that Ca 2+ is also an important positive regulator of tumorigenesis in GBM [START_REF] Robil | Glioblastoma and calcium signaling -analysis of calcium toolbox expression[END_REF][START_REF] Leclerc | Calcium signaling orchestrates glioblastoma development: facts and conjunctures[END_REF]. Interestingly, screening of the Prestwick Chemical library identified bisacodyl, an organic compound used as a stimulant laxative drug, with cytotoxic effect on quiescent GSLCs [START_REF] Zeniou | Chemical library screening and structure-function relationship studies identify bisacodyl as a potent and selective cytotoxic agent towards quiescent human glioblastoma tumor stem-like cells[END_REF]. Bisacodyl inhibits Ca 2+ release from inositol 1,4,5-triphosphate-dependent Ca 2+ stores without affecting the store-operated Ca 2+ entry (SOCE) [START_REF] Dong | Bisacodyl and its cytotoxic activity on human glioblastoma stemlike cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling[END_REF]. These data exemplify the fact that Ca 2+ channels, pumps, and exchangers may represent potential therapeutic targets. In this review, we will summarize the current knowledge regarding the quiescent GSLCs with respect to Ca 2+ signaling and describe an original mechanism by which Ca 2+ can activate some genes involved in the prognosis of GBM in order to propose new strategies to explore the molecular basis of GBM development for therapeutic issues.

TRANSITION FROM PROLIFERATION TO QUIESCENCE AND Ca 2+ SIGNALING Quiescent cells are non-proliferative cells, arrested in a specific phase of the cell cycle called G0 [START_REF] Coller | A new description of cellular quiescence[END_REF]. Quiescence is not a prolonged G1 phase and in contrary to the cellcycle arrest observed in differentiation or senescence, it is reversible. Transcriptional profiling data reveal that quiescent stem cells are characterized by a common set of genes which are either downregulated, these are genes associated with cell-cycle progression (i.e., CCNA2, CCNB1, and CCNE2), or upregulated and classified as tumor suppressors, including the cyclin-dependent kinase inhibitor p21 (CDKN1A) and the G0/G1 switch gene 2 (G0S2) [START_REF] Yamada | The cytosolic protein G0S2 maintains quiescence in hematopoietic stem cells[END_REF][START_REF] Cheung | Molecular regulation of stem cell quiescence[END_REF]. Quiescence represents a strategy for GSLCs to evade killing. It is thus vital to better characterize the quiescent GSLCs and to understand the mechanisms involved in the transition from a proliferative to a quiescence state. Quiescence is actively regulated by signals provided by the stem cell microenvironment. In GBM, quiescent cells are found close to necrotic tissues, in specific niches characterized by a hypoxic [START_REF] Pistollato | Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma[END_REF][START_REF] Persano | The three-layer concentric model of glioblastoma: cancer stem cells, microenvironmental regulation, and therapeutic implications[END_REF][START_REF] Ishii | Histological characterization of the tumorigenic "peri-necrotic niche" harboring quiescent stem-like tumor cells in glioblastoma[END_REF] and acidic microenvironment [START_REF] Garcia-Martin | High resolution pHe imaging of rat glioma using pH-dependent relaxivity[END_REF][START_REF] Honasoge | Autocrine regulation of glioma cell proliferation via pH e -sensitive K + channels[END_REF].

A recent study suggests that Ca 2+ is an important regulator of the balance between quiescence and proliferation in hematopoietic stem cell (HSC) [START_REF] Umemoto | Ca 2+ -mitochondria axis drives cell division in hematopoietic stem cells[END_REF]. In HSCs, re-entry into cell-cycle requires Ca 2+ influx through Cav1 voltage-dependent Ca 2+ channel and the resultant activation of mitochondria. Recent findings in our group showed that Ca 2+ signaling is also required for GBM stem cells quiescence. On GSLCs lines, established from surgical resections of primary GBMs, we showed that change in Ca 2+ homeostasis is an important actor of the transition from proliferation to quiescence. In order to analyze the signals underlying this switch, we modified the culture condition by lowering the extracellular pH from pH 7.5 to 6.5. GSLCs kept in such conditions for 5 days enter G0. This simple protocol allowed to reversibly maintain GSLCs in a proliferating or in quiescent state [START_REF] Zeniou | Chemical library screening and structure-function relationship studies identify bisacodyl as a potent and selective cytotoxic agent towards quiescent human glioblastoma tumor stem-like cells[END_REF][START_REF] Aulestia | Quiescence status of glioblastoma stem-like cells involves remodelling of Ca 2+ signalling and mitochondrial shape[END_REF]. A RNAseq analysis, focusing on the Ca 2+ toolkit genes [START_REF] Robil | Glioblastoma and calcium signaling -analysis of calcium toolbox expression[END_REF], established the transcriptional profiles of these proliferative and quiescent GSLCs and revealed that genes regulating plasma membrane Ca 2+ channels (CACNA2D1 and ORAI2) and mitochondrial Ca 2+ -uptake (MCU, MICU1, MICU2, and VDAC1) are downregulated in quiescence while others are upregulated (CACNB1, CAPS, and SLC8B1). A functional analysis through a bioluminescent Ca 2+ imaging approach showed that quiescence in GSLCs does not involve Cav1 channels like in HSCs, but is rather due to the modification of the kinetics of the store-operated Ca 2+ entry (SOCE), mediated by plasma membrane ORAI channels associated with the ER membrane protein STIM1. The inhibition of store-operated channels (SOC) by SKF96365 triggers quiescence, further supporting the crucial role of SOC in quiescence in GSLCs. Interestingly, the use of bioluminescent Ca 2+ reporter targeted to mitochondria revealed that this change in SOCE kinetics is due to an increased capacity of quiescent GSLCs' mitochondria to capture Ca 2+ and not to the modification of the SOCE mechanism itself [START_REF] Aulestia | Quiescence status of glioblastoma stem-like cells involves remodelling of Ca 2+ signalling and mitochondrial shape[END_REF]. These data highlight the importance of mitochondria as regulator of Ca 2+ homeostasis.

Over the past decade, many studies have identified changes in the expression levels of proteins involved in Ca 2+ homeostasis such as Ca 2+ channels, pumps, and exchangers and established that some of these proteins contribute to tumorigenesis through regulation of proliferation, migration, or apoptosis [START_REF] Monteith | Calcium channels and pumps in cancer: changes and consequences[END_REF][START_REF] Leclerc | Calcium signaling orchestrates glioblastoma development: facts and conjunctures[END_REF]. As a second messenger, Ca 2+ is also an important regulator of gene expression. This occurs either indirectly, via changes in the transactivating properties of transcription factors following the activation of Ca 2+ -dependent kinases and/or phosphatases [START_REF] Dolmetsch | Signaling to the nucleus by an L-type calcium channelcalmodulin complex through the MAP kinase pathway[END_REF][START_REF] West | Calcium regulation of neuronal gene expression[END_REF][START_REF] Kornhauser | CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events[END_REF][START_REF] Spotts | Time-lapse imaging of a dynamic phosphorylation-dependent protein-protein interaction in mammalian cells[END_REF], or directly via EF hand Ca 2+ -binding proteins which belongs to a group of four proteins (KCNIP1-4) [START_REF] Mellström | Ca 2+ -operated transcriptional networks: molecular mechanisms and in vivo models[END_REF]. The identification of new therapeutic targets now requires not only to target the identified proteins but also to analyze the molecular mechanisms responsible for the changes in gene expression observed in cancer cells. In this review, we choose to focus on the direct mode of action of Ca 2+ on transcription with the implication of KCNIPs in GBM.

THE FAMILY OF NEURONAL Ca 2+ SENSORS: KCNIPs

Potassium channel-interacting proteins (KCNIPs), which constitute the class E of Ca 2+ sensor family, are globular proteins of 217-270 amino acids in size, with variable N-and C-termini and a conserved core domain containing four EF-hand Ca 2+binding motifs (EF-1, EF-2, EF-3, and EF-4). Among the four EF hands, EF-1 is not able to bind Ca 2+ [START_REF] Buxbaum | Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment[END_REF][START_REF] Carrión | DREAM is a Ca2+-regulated transcriptional repressor[END_REF][START_REF] An | Modulation of A-type potassium channels by a family of calcium sensors[END_REF]. Drosophila melanogaster has a single Kcnip, whereas mammals have four KCNIPs (KCNIP1-4) and several alternatively spliced variants [START_REF] Burgoyne | Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling[END_REF]. In mammals, the four KCNIPs are predominantly expressed in adult brain, with specific or overlapping patterns according to the tissues [START_REF] Rhodes | KChIPs and Kv4 subunits as integral components of A-Type potassium channels in mammalian brain[END_REF][START_REF] Xiong | Differential distribution of KChIPs mRNAs in adult mouse brain[END_REF][START_REF] Pruunsild | Structure, alternative splicing, and expression of the human and mouse KCNIP gene family[END_REF]. KCNIP3, also called calsenilin, KChIP3, and DREAM [i.e., Downstream Regulatory Element (DRE) Antagonist Modulator] is also found in the thyroid gland [START_REF] Dandrea | The transcriptional repressor DREAM is involved in thyroid gene expression[END_REF][START_REF] Rivas | The DREAM protein is associated with thyroid enlargement and nodular development[END_REF] and in the hematopoietic progenitor cells [START_REF] Sanz | Interleukin 3-dependent activation of DREAM is involved in transcriptional silencing of the apoptotic hrk gene in hematopoietic progenitor cells[END_REF]. KCNIP2 and KCNIP3 are found in T and B lymphocytes [START_REF] Savignac | Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression[END_REF][START_REF] Savignac | Increased B cell proliferation and reduced Ig production in DREAM transgenic mice[END_REF]. During mouse development, Kcnip3 transcript first occurs at E10.5 [START_REF] Spreafico | Mouse DREAM/Calsenilin/KChIP3: gene structure, coding potential, and expression[END_REF] and Kcnip1, 2, and 4 are not detected before E13 [START_REF] Pruunsild | Structure, alternative splicing, and expression of the human and mouse KCNIP gene family[END_REF]. In the fish Danio rerio, the embryonic expressions of kcnip1b and kcnip3 are not detectable before somitogenesis [START_REF] Stetsyuk | Calsenilin is required for endocrine pancreas development in zebrafish[END_REF] and in the amphibian Xenopus laevis among the four kcnips, only kcnip1 is expressed at all developmental stages, from fertilized egg to the tadpole stages. By contrast, the transcripts for kcnip2, kcnip3, and kcnip4 are expressed at later stages, after the specification of neural territories [START_REF] Néant | Kcnip1 a Ca2+-dependent transcriptional repressor regulates the size of the neural plate in Xenopus[END_REF].

KCNIP proteins are known to control gene transcription directly by binding, via a Ca 2+ -dependent mechanism, to specific DNA sites, called DRE, of target genes. DRE sites are localized in the proximal 5 sequence of the gene, downstream of the TATA box and upstream of the start codon, with the sequence GTCA forming the central core of the DRE site [START_REF] Carrión | DREAM is a Ca2+-regulated transcriptional repressor[END_REF][START_REF] Ledo | The DREAM-DRE interaction: key nucleotides and dominant negative mutants[END_REF]. This mechanism has been particularly well described for KCNIP3 (DREAM). When the intracellular Ca 2+ level is low, KCNIP3 is bound as tetramer to the DRE sites, acting mainly as a transcriptional repressor. An increase in intracellular Ca 2+ leads to dissociation of the KCNIP3 tetramer from its DRE site, thus allowing transcription [START_REF] Carrión | DREAM is a Ca2+-regulated transcriptional repressor[END_REF]. KCNIP3 can affect transcription by acting either as a transcriptional repressor [START_REF] Carrión | DREAM is a Ca2+-regulated transcriptional repressor[END_REF][START_REF] Link | Day-night changes in downstream regulatory element antagonist modulator/potassium channel interacting protein activity contribute to circadian gene expression in pineal gland[END_REF] or activator [START_REF] Scsucova | The repressor DREAM acts as a transcriptional activator on Vitamin D and retinoic acid response elements[END_REF][START_REF] Cebolla | DREAM Mediates cAMP-dependent, Ca2+-induced stimulation of GFAP gene expression and regulates cortical astrogliogenesis[END_REF]. In a more recent study, KCNIP3 has been shown to be required for human embryonic stem cells (hESCs) survival and to maintain hESCs pluripotency [START_REF] Fontán-Lozano | Impact of transient down-regulation of DREAM in human embryonic stem cell pluripotency[END_REF]. KCNIP3 was initially the only Ca 2+ sensor known to bind to DRE sites and to directly regulate transcription in a Ca 2+ -dependent manner [START_REF] Mellström | Ca2+-dependent transcriptional repression and derepression: DREAM, a direct effector[END_REF]. However, all the four KCNIPs exhibit DRE-binding site affinity as homo or heterotetramers and act as Ca 2+ -dependent transcriptional regulators [START_REF] Osawa | Calcium-regulated DNA binding and oligomerization of the neuronal calcium-sensing protein, calsenilin/DREAM/KChIP3[END_REF][START_REF] Craig | The metal-binding properties of DREAM: evidence for calcium-mediated changes in DREAM structure[END_REF][START_REF] Link | Day-night changes in downstream regulatory element antagonist modulator/potassium channel interacting protein activity contribute to circadian gene expression in pineal gland[END_REF], allowing functional redundancy. KCNIP2 and KCNIP3 interactions are indirectly evidenced by two-hybrid and immunoprecipitation experiments [START_REF] Savignac | Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression[END_REF] and by the fact that KCNIP3 and KCNIP2 are both able to physically interact with EF-hand mutated KCNIP3 and that such associations still inhibit DRE-dependent gene expression [START_REF] Gomez-Villafuertes | Downstream regulatory element antagonist modulator regulates Ca2+ homeostasis and viability in cerebellar neurons[END_REF][START_REF] Savignac | Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression[END_REF]. In vivo studies also argue for the existence of compensatory mechanisms and the formation of functional KCNIP heterotetramers. Particularly, while in cortico-hippocampal neurons from Kcnip3 knockdown mice, the expression levels of KCNIP3 target genes such as Npas4 and cfos are not significantly modified, the additional invalidation of Kcnip2 with an antisense lentiviral vector (in this Kcnip3 KO context) results in a significant increase in the expression of these KCNIP3-dependent target genes [START_REF] Mellström | DREAM controls the on/off switch of specific activity-dependent transcription pathways[END_REF].

In amphibian embryos, we demonstrated that Kcnip1 binds DRE sites in a Ca 2+ -dependent manner. Kcnip1 is the earliest kcnip gene expressed in X. laevis embryo. Its transcripts are timely and spatially present in the presumptive neural territories. In this in vivo model, loss of function experiments indicate that Kcnip1 is a Ca 2+ -dependent transcriptional repressor that controls the size of the neural plate by regulating the proliferation of neural progenitors [START_REF] Néant | Kcnip1 a Ca2+-dependent transcriptional repressor regulates the size of the neural plate in Xenopus[END_REF].

KCNIP PROTEINS IN GLIOBLASTOMA

To the best of our knowledge, no published work has analyzed the expression of KCNIPs in GSLCs or more generally in cancer stem cells. Using the UALCAN server [START_REF] Chandrashekar | UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses[END_REF], it was possible to compare gene expression in normal brain tissues versus GBM multiform. KCNIP1-4 are expressed in normal tissues at comparable levels. Interestingly, in GBM tissues while KCNIP1 is significantly upregulated compared to its levels in normal brain tissues, KCNIP2 and KCNIP3 are strongly downregulated (Table 1). Although KCNIP4 expression appears downregulated in GBM, the results are not statistically significant. This is probably due to large variability of KCNIP4 expression in normal brain tissues and the small number of samples analyzed. In terms of survival, only KCNIP2 expression is relevant. Among GBM patients, those with high KCNIP2 expression appear to have a significant reduction in their overall survival time (UALCAN analysis). A recent study incidentally provides additional information on KCNIP expression in BT189 GSLC [START_REF] Wang | ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways[END_REF]. Wang and coworkers analyzed the function of ING5, an epigenetic regulator overexpressed in GBM, and showed that ING5 promotes GSLCs self-renewal capabilities. Using the fluorescent Ca 2+ probe fluo3, these authors showed that [Ca 2+ ]i increases in cells overexpressing ING5. This increase Gene expression is presented as a number of transcripts for each KCNIP genes per million of total transcripts. Data extracted using the UALCAN server (http://ualcan.path.uab.edu/index.html). Genes and proteins symbols are formatted according to the specific conventions particular to each organism (www.biosciencewriters.com). S1 in [START_REF] Wang | ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways[END_REF]. These data suggest a role of KCNIP proteins in stemness maintenance and dormant status of the GSLCs. The importance of KCNIPs in GBM is further emphasized by the presence of potential DRE sites within the proximal promoter of MCU and MICU2, two genes downregulated in quiescent GSLCs [START_REF] Aulestia | Quiescence status of glioblastoma stem-like cells involves remodelling of Ca 2+ signalling and mitochondrial shape[END_REF] and within the proximal promoters of TRPC5, TRPC4, and TRPM1, genes from the TRP family upregulated by the epigenetic factor ING5 in BT189 GSLC [START_REF] Wang | ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways[END_REF]; Table 2).

REGULATION OF GBM PROGNOSIS GENES BY KCNIP PROTEINS

Ion channels are now considered as important actors in cancers. Recent studies using microarray datasets of glioma samples obtained from the CGGA (Chinese Glioma Genome Atlas) and the TCGA (The Cancer Genome Atlas) identified genes belonging to the Ca 2+ signaling machinery as new candidate genes that can predict GBM patients with high risk of unfavorable outcome [START_REF] Wang | A three ion channel genes-based signature predicts prognosis of primary glioblastoma patients and reveals a chemotherapy sensitive subtype[END_REF][START_REF] Zhang | Targetable T-type calcium channels drive glioblastoma[END_REF][START_REF] Zhang | A 63 signature genes prediction system is effective for glioblastoma prognosis[END_REF]. These genes, listed in Table 3, are ion channels a Position upstream from the ATG; S, sense; AS, anti-sense; b putative DRE sites in close proximity; c two putative DRE sites in tandem. NF, not found, in accordance with the criteria in proximal 5 upstream sequence between the tata box and the start codon (see details in text).

FIGURE 1 | Putative DRE sites for two prognosis genes KCNN4 and CAMK2A. The proximal promoters of primates (human, chimpanzee, and rhesus monkey) and mouse are highly conserved for KCNN4 and CAMK2A genes, the putative DRE-binding sites within these proximal promoters are positioned regarding to ATG (numbers in italic), the lengths of the 5 fragment sequences are expressed in bp, and the yellow arrow gives the sequence orientation (see Table 3 for DRE sequence details). A point mutation (T to C) in a "sense" DRE site within rhesus monkey sequence is mentioned by the gray arrow.

genes namely CACNA1H, a T-type Ca 2+ channel (Cav3.2); KCNN4, a potassium Ca 2+ -activated channel (KCa3.1); KCNB1, a voltage-gated potassium channel (Kv2.1); KCNJ10, a potassium Ca 2+ -activated channel (Kir4.1); and classified as Ca 2+ -binding protein; PRKCG, Ca 2+ -dependent serine/threonine protein kinase Cγ (PKCγ); PRKCB, Ca 2+ -dependent serine/threonine protein kinase Cβ (PKCβ); and CAMK2A, the Ca 2+ -calmodulindependent protein kinase IIα. KCNIP proteins are known to control gene transcription directly by binding to DRE sites. To test whether KCNIP proteins may be involved in the regulation of the expression of these selected prognosis genes, we searched for the presence of DRE sites within their proximal promoters.

The CACNA1H and PRKCB genes present both one DRE potential site in their proximal promoter and KCNB1 presents two DRE-binding sites (Table 3). More exciting are the three and four putative DRE sequences exhibited by CAMK2A and KCNN4, respectively, ideally positioned between the TATA box and the start codon, within the highly conserved sequence of proximal promoter in primates (Figure 1). The CAMK2A proximal promoter is also particularly conserved in mouse compared to human (87%), their DRE sites respect orientation and repartition, even for tandem organization. This promising observation has to be tested for KCNIP binding efficiency.

Recent evidence argues for the existence of functional DRE sites within the CAMK2A proximal promoter. KCNIP3 mutants with two amino acids substitution in the EF-hands two, three, and four are unable to respond to Ca 2+ and function as a constitutively dominant active (daDREAM) transcriptional repressor [START_REF] Savignac | Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression[END_REF]. In transgenic mice with neuronal expression of this daDREAM, the CAMK2A mRNA level is reduced by 1.7-fold compared to wild type [START_REF] Benedet | Transcriptional repressor DREAM regulates trigeminal noxious perception[END_REF].

Mouse promoter for KCNN4 is conserved (79%), but in a lesser extend concerning DRE sequences. These sequence alignments for proximal promoters let guess a putative regulatory role of KNCIPs in the expression of some prognosis genes in GBM. Of note, not all of these prognosis genes exhibit DRE-like sites, as no DRE putative sequence was detected for KCNJ10 or PRKCG (Table 3), suggesting that KCNIPs are not the only transcriptional regulators directly implicated in the regulation of these prognosis genes, but the hypothesis of their contribution remains attractive.

It is noteworthy that the previous results were obtained using transcriptomic data issued from DNA chips. When using the portal UALCAN [START_REF] Chandrashekar | UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses[END_REF] interfaced with the TCGA data base of transcriptomic cancer profiles obtained by RNA-seq techniques, only CACNA1H and KCNN4 expression levels are correlated with significant differences in survival curves. It is noticeable that these two genes present one and three DRE sites, respectively. Anyhow, the presence of these putative DRE sites on prognosis genes, suggests that remodeling of Ca 2+ homeostasis in GBM stem cells may contribute to the alteration of the expression of these prognosis genes. These preliminary observations urge for a more complete analysis taking into account the high level of false negatives when using the transcriptomic signatures built from DNA chip data.

PERSPECTIVES/PROSPECT ON KCNIPS IN GBM

Although no specific data are available for KCNIPs' function in GBM or even cancers, one can speculate taking into account published functions of KCNIP in other cell types. KCNIPs are in fact multifunctional EF hand Ca 2+ -binding proteins and according to their interaction partners and subcellular localization one can discriminate at least three main functions: (1) regulation of cellular excitability, (2) regulation of intracellular signaling, and (3) control of transcription.

Control of Cellular Excitability

The control of cellular excitability which involves the formation of a macromolecular signaling complex between KCNIP1 or 2, the A-type Kv4 potassium channel, and the T-type Ca 2+ channel Cav3 (Anderson et al., 2010a,b) is unlikely to occur in GSLCs. Indeed, investigation of the electrophysiological properties of glioma cells revealed the absence of A-type potassium channels in these cells [START_REF] Bordey | Electrophysiological properties of human astrocytic tumor cells In situ: enigma of spiking glial cells[END_REF]. Therefore, only the two other functions of KCNIP may be relevant to GBM physiology.

Regulation of Intracellular Ca 2+ Signaling

In cardiomyocytes, KCNIP2 participates in the modulation of Ca 2+ release through ryanodine receptors (RyR) by interacting with the ryanodine modulator, presenilin [START_REF] Nassal | KChIP2 regulates the cardiac Ca2+ transient and myocyte contractility by targeting ryanodine receptor activity[END_REF].

The presenilin/KCNIP3 complex has also been shown to modulate IP3-mediated Ca 2+ release [START_REF] Leissring | Calsenilin reverses presenilin-mediated enhancement of calcium signaling[END_REF].

We have already shown that the unique drug able to kill quiescent GSLCs acts through a modulation of IP3 signaling [START_REF] Dong | Bisacodyl and its cytotoxic activity on human glioblastoma stemlike cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling[END_REF].

Control of Transcription

As mentioned above, all KCNIPs can bind to DRE sites on DNA and directly control transcription. KCNIP3 (DREAM) can also interact with other transcription factors such as CREB and therefore affects transcription of genes that do not contain DRE sites (review in [START_REF] Rivas | Building the DREAM interactome[END_REF]. Interestingly, in cardiomyocytes, it has been shown that the complex Ca 2+ /CAMK2 regulates nuclear translocation of KCNIP3 [START_REF] Ronkainen | Ca 2+ -calmodulin-dependent protein kinase II represses cardiac transcription of the L-type calcium channel α 1C -subunit gene (Cacna1c) by DREAM translocation: CaMKII represses Cacna1c by DREAM translocation[END_REF]. As CAMK2A has been identified as a prognosis gene in GBM (Table 3), such a mechanism is likely to occur in GBM.

In conclusion, since no experimental data exists for the moment in the literature concerning the function of KCNIP family in GBM, this opens a new field of research. In other models, KCNIPs have pleiotropic effects. Their well-known role as transcriptional repressors, and the presence of DRE sites in the promoter region of some GBM prognosis genes argue for a transcriptional function of KCNIPs in GBM. However, nontranscriptional roles have also to be considered more closely in the future.

TABLE 1 |

 1 KCNIP genes expression in glioblastoma multiform.

	Gene	Gene expression in normal	Gene expression in glioblastoma	Statistical significance at 0.05
		brain tissues (n = 5)	multiform (GBM) tissues (n = 156)
		maximum -median -minimum	maximum -median -minimum
	KCNIP1	42.014 -38.869 -34.986	229.234 -50.603 -0.603	1.829 E-04
	KCNIP2	85.765 -68.456 -16.25	23.856 -6.02 -0.222	4.978 E-02
	KCNIP3	51.355 -51.275 -49.132	33.57 -8.244 -0.43	4.279 E-09
	KCNIP4	77.262 -53.813 -10.084	25.877 -4.346 -0.501	7.312 E-02

TABLE 2 |

 2 Candidate genes with putative DRE site and expressed in GSLCs.

	Gene	Function	Expression in	Reference	Number of putative	Sense/position	Sequence in Homo sapiens (the
			GSLCs		DRE sites	in bp a	core sequence is underlined)
	MCU b	Mitochondrial	Downregulated in	Aulestia et al., 2018	3	S/-240	5 tttgggtgtcaattatgggt 3 5
		calcium uniporter	the quiescent state			AS/-207	cccgtaattgactatgtccc 3 5
						S/-101	caactcagtcaagggcttta 3
	MCUb	Mitochondrial			2	AS/-70 AS/-36	5 ccaggcgctgacgaggagcc 3 5
		calcium uniporter					tgcgccgctgacgcctgcgg 3
		beta subunit
	MICU1	Mitochondrial			NF
		calcium uptake 1
	MICU2	Mitochondrial			1	AS/-199	5 ggatgggatgacaggaagag 3
		calcium uptake 2
	VDAC1	Voltage-dependent			NF
		anion channel 1
	TRPC3	Transient receptor	Upregulated by	Wang et al., 2018	NF
		potential cation	ING5
		channel subfamily
		C member 3
	TRPC4	Transient receptor			4	AS/-620	5 ggctggatgacggctggctg 3 5
		potential cation				AS/-582	cactggctgacctcaagcag 3 5
		channel subfamily				S/-355 S/-76	atccgctgtcagccgtggga 3 5
		C member 4					ccgcgccgtcagtcctcgga 3
	TRPC5 b	Transient receptor			4	S/-478 S/-465	5 cctacagtgtcagctacccc 3 5
		potential cation				S/-451	ctacccctgtcagtttcccc 3 5
		channel subfamily				AS/-421	ttccccgtgtcagtttcttc 3 5
		C member 5					attgtgtgtgactggctgcg 3
	TRPM1	Transient receptor			1	S/-34	5 ccgagggagtcagcagggtg 3
		potential cation
		channel subfamily
		M member 1

a Position upstream from the ATG; S, sense; AS, anti-sense; b putative DRE sites in close proximity. NF, not found, in accordance with the criteria in proximal 5 upstream sequence between the tata box and the start codon (see details in text).

TABLE 3 |

 3 Candidate genes associated with unfavorable prognosis in GBM.

	Gene	Function	Role in GBM	Reference	Number of putative	Sense/position in	Sequence in Homo sapiens
					DRE sites	bp a	(core sequence underlined)
	CACNA1H	Cav3.2; T-type	Over-expression	Zhang et al., 2017	1	AS/-72	5 tccgcggtgaccgcgccg3
		Ca 2+ channel;	associated with
		Ca 2+ homeostasis	worse prognosis
	KCNN4 b	KCa3.1; voltage-	Over-expression	Turner et al., 2014;	4	S/-359 AS/-334	5 ggtgtgtgtcacaaagtac3
		independent	associated with	Wang et al., 2016		S/-166 AS/-94	5 ttgtgtgtgacaaagccca3
		potassium	worse prognosis,				5 cctggccgtcaccactccc3
		Ca 2+ -activated	confers invasive				5 agcaggctgacgacctgca3
		channel	phenotype.
	KCNB1	Kv2.1; potassium	Downregulated in	Wang et al., 2016	2	AS/-137 AS/-48	5 acggccgtgacgcgcgccc3
		voltage-gated	gliomas. Correlated				5 cgtcgagtgacagcggcct3
		channel; delayed	with malignant
		rectifier potassium	progression when
		channel	associated with
			KCNN4 and
			KCNJ10
	KCNJ10	Kir4.1; potassium	Downregulated in		NF
		voltage-gated	gliomas, correlated
		channel;	with malignant
		ATP-dependent	progression when
		inwardly rectifier;	associated with
		potassium buffering	KCNN4 and
		in glial cells	KCNB1
	PRKCG	Protein kinase Cγ;	Belong to a	Zhang et al., 2018	NF
		serine/threonine	co-expression
		protein kinase	network genes that
		activated by Ca 2+	can serve as
		and diacylglycerol	prognostic factors
			for GBM
	PRKCB	Protein kinase Cβ;			1	AS/-168	5 gggcgagtgacagccccgg3
		serine/threonine
		protein kinase
		activated by Ca 2+
		and diacylglycerol
	CAMK2A c	Ca 2+ -calmodulin-			3	AS/-192 S/-133	5 tggatgctgacgaaggctc3
		dependent protein				S/-129	5 ggctcgtcagtcaaaccgg3
		kinase IIα

Frontiers in Molecular Neuroscience | www.frontiersin.org 2 December 2018 | Volume 11 | Article 472

Frontiers in Molecular Neuroscience | www.frontiersin.org 3 December 2018 | Volume 11 | Article 472

Frontiers in Molecular Neuroscience | www.frontiersin.org 4 December 2018 | Volume 11 | Article 472

Frontiers in Molecular Neuroscience | www.frontiersin.org 5 December 2018 | Volume 11 | Article 472

Frontiers in Molecular Neuroscience | www.frontiersin.org 6 December 2018 | Volume 11 | Article 472

Frontiers in Molecular Neuroscience | www.frontiersin.org

December 2018 | Volume 11 | Article 472

Frontiers in Molecular Neuroscience | www.frontiersin.org 9 December 2018 | Volume 11 | Article 472

FUNDING

This work was supported by the Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg, Université Toulouse 3, by a joint grant from the Agence Nationale de la Recherche (ANR) given between France and Hong Kong to CL, JH, and MM (CalciumGlioStem ANR-13-ISV1-0004 and A-HKUST601/13), SATT Conectus (M-CK), and has been performed within the LABEX ANR-10-LABX-0034_Medalis and received a financial support from French Government managed by "Agence Nationale de la Recherche" under "Programme d'investissement d'avenir." FA was supported by a grant from the ANR CalciumGlioStem.

AUTHOR CONTRIBUTIONS

IN, JH, M-CK, FA, MM, and CL designed the experiments. IN, FA, and CL performed and analyzed the experiments. IN, JH, M-CK, MM, and CL wrote the manuscript. JH, MM, and CL analyzed the data, provided financial support, and the final approval of manuscript. All authors reviewed the manuscript.

Conflict of Interest Statement:

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Catherine Meur-Ferec

Elisabeth Guillou

Interest of Social Representations Theory to grasp coastal vulnerability and to enhance coastal risk management

Keywords: coastal risks, vulnerability, Social Representations Theory, social psychology, geography Resumen

This theoretical paper provides a new perspective on coastal vulnerability analysis by combining geography and psycho-social approaches. Most studies on perceptions of coastal risks report that people who are exposed have a low level of perceived vulnerability (they are not anxious), strong place attachment (they love their living place and want to live close to the sea) and are resistant to changes in adaptation strategies (they do not want to move away). For natural scientists and managers, these findings usually appear as paradoxes that enhance vulnerability and lead to these people being labelled 'irrational', 'in denial', 'uninformed' or 'uneducated'. Based on our long-term studies among coastal inhabitants in France, we believe that using Social Representations Theory (SRT) in this context enables us to go beyond these preconceived and individual-centred ideas towards a more contextualized view. This position extends theoretical risk/vulnerability research and is applicable to coastal risk management.

emplear la Teoría de Representaciones Sociales en este contexto nos permite ir más allá de estas ideas preconcebidas e individualistas, hacia una visión más contextualizada. Esta posición amplía el alcance de la investigación teórica sobre riesgo/vulnerabilidad y es aplicable a la gestión de riesgos en el litoral.

Palabras clave: riesgos costeros, vulnerabilidad; Teoría de las Representaciones Sociales; psicología social; geografía Since 2009, Psyecology publishes all articles bilingually. However, this Special Issue is different, and there will be no Spanish translation of this article. Please read the issue's Introduction [URL/DOI] for more information about this change, which will only affect this issue. All articles published in the future will continue to be published bilingually. / Desde 2009, Psyecology publica todos los artículos en formato bilingüe. Sin Cedex 3, France. E-mail: elisabeth.guillou@univ-brest.fr

Research context: coastal vulnerability<<t/s: Head1>>

In today's context of growing urbanization and climate change, coastlines are especially vulnerable to erosion and sea flooding (e.g., [START_REF] Birkmann | Measuring vulnerability to natural hazards: Towards disaster resilient societies[END_REF]IPCC, 2013;[START_REF] Nicholls | Sea level rise and its impact on coastal zones[END_REF]. On the one hand, the natural coastal dynamic is frequently modified by human actions, and is globally affected by climate change-related sea level rises. In terms of erosion and sea flooding risks, this situation exacerbates hazards: coastlines tend to retreat inland and lowlands are flooded more often. On the other hand, residential and tourism settlements are becoming more and more concentrated near the sea as people are attracted to the proximity of waterfront amenities. As a result, there is an increase of vulnerability for coastal territories, a trend that is likely to grow in the coming decades.

In consequence, because coastal vulnerability is multifactorial, to understand it, we must take into account a systemic approach [START_REF] Hellequin | Perceptions du risque de submersion marine par la population du littoral languedocien: Contribution à la l'analyse de la vulnérabilité côtière[END_REF]Henaff & Philippe, 2014;[START_REF] Meur-Ferec | Coastal risks in France: An integrated method for evaluating vulnerability[END_REF]. This approach brings together societies and nature in an advanced interdisciplinary study of coastal risks.

We consider vulnerability to be the result of four main interactive components: (i) hazards (natural processes of erosion and sea flooding, sometimes reinforced by human actions);

(ii) stakes (what is at risk of being lost, people and goods exposed to hazards); (iii) management (public risk-management policies, protection/safeguarding measures); and

(iv) perception/representations (of risk, place and adaptation among stakeholders and inhabitants) (see Figure 1).

In vulnerability studies, the 'representations' component often seems to be neglected (Becerra & Peltier, 2009). Our article highlights the importance of this component in the coastal vulnerability model and proposes a theoretical reflection based on the development of researches, combining the geographical and psychological views. In particular, we show that the integration of Social Representations Theory (SRT) [START_REF] Moscovici | La psychanalyse, son image et son public[END_REF][START_REF] Moscovici | Why a theory of social representations[END_REF] in the analysis of vulnerability helps to understand individuals' positions towards coastal risks and preferred strategies.

Our theoretical approach: risk and social representations<<t/s: Head1>>

Many studies about risk perception differentiate the layperson from the expert. They compare the layperson's perception with the expert's assessment or with an unquestionable measured physical process ('scientific' measures) [START_REF] Slovic | The perception of risk[END_REF]. Consequently, this approach underlines the differences between the two forms of thought (layperson/expert) in risk conception. These differences are interpreted in terms of cognitive biases in individual perceptions.

Another approach, based on SRT, aims to understand how people represent risks according to their groups of belonging which enrol them in societies' power dynamics [START_REF] Breakwell | Mental models and social representations of hazards: The significance of identity processes[END_REF][START_REF] Joffe | Risk: From perception to social representation[END_REF]Michel-Guillou & Meur-Ferec, 2016b). Social representations consist of common sense knowledge [START_REF] Moscovici | La psychanalyse, son image et son public[END_REF][START_REF] Moscovici | Why a theory of social representations[END_REF]) that allows individuals to understand their environment, communicate in it and act on it. This social thought, anchored in a particular culture, enables people to find meaning in what seems strange or unusual. Representations therefore enable communication through the sharing of ideas, values and beliefs [START_REF] Doise | Debating social representations[END_REF]. Moscovici developed his theory to understand how scientific theories and concepts are appropriated by common sense and allow the transformation the 'unfamiliar', the novelty or the strange, into a familiar sense for people.

It is not our intention in this article to develop more the theory of social representations [START_REF] Moscovici | La psychanalyse, son image et son public[END_REF][START_REF] Moscovici | Why a theory of social representations[END_REF], which has been largely developed elsewhere (e.g., [START_REF] Breakwell | Integrating paradigms, methodological implications[END_REF]Deaux & Philogène, 2001). We just focus on the interest of this theory for studying 'risks'. The risk representations approach takes into account the social-cultural context in which individuals who are likely to be affected by a given risk live (rather than pre-defined categories such as age, gender, education level, etc.). It proposes linking the representations with other concepts such as identity or place identity. On the matter, Breakwell's theory, linking social representations, risks and identity processes, is especially relevant. In the Identity Process Theory [START_REF] Breakwell | Mental models and social representations of hazards: The significance of identity processes[END_REF], social representations contribute to the social or personal identity. But in return, identity can play a role in the construction of representations, particularly in the case of uncertainty and changes. Changes in environment may threaten the identity of individuals. In response to that threat, coping strategies are implemented to protect, often by a change in social representation, to incorporate the novelty.

The link between identity and social representations was highlighted in several researches on place identity [START_REF] Bonaiuto | Identity processes and environmental threat: The effects of nationalism and local identity upon perception of beach pollution[END_REF][AQ1]Devine-Wright, 2009). In these studies, the researchers showed that there are 'objectives' characteristics (social, economic, environmental …) to define a place. But when changes or disruption appear, these are not the objective characteristics which play a major role in the position towards these changes. The representation of the characteristics of this place and the way in which these characteristics contribute to the construction of identity are important in the interpretation of changes (in terms of positive or negative). This representation can thus explain why in some cases the risk is perceived (objectived) for some groups and not perceived for other groups. Thus, to understand the dynamics of groups and their concern about a given risk, it seems important to study the social representations of the different groups involved, in order to know their positions and their interpretation of the situation.

Consequently, SRT was chosen here to explore representations of coastal risks. We believe that when this risk is seen as a danger, it can threaten identity. A social construction process consequently takes place to deal with this danger. This symbolic coping involves appropriation of the object of risk (submersion) and familiarization with the unfamiliar to make it intelligible and communicable [START_REF] Wagner | Killer tomatoes! Collective symbolic coping with biotechnology[END_REF], which in turn may lead to the construction of a social representation of coastal risks.

Our research objective is to propose another theoretical approach to understand the positions and the social logics of inhabitants who live in exposed locations towards these risks, and their preferences in terms of adaptation strategies. This knowledge is an important factor for explaining some perceived paradoxes and overcoming some of the difficulties involved in the implementation of public policies. Consequently, this paper synthetically develops three topics based on three perceived paradoxes by natural scientists and managers: (i) how individuals can be aware of but not worried about risks; (ii) how individuals can be strongly place-attached but also think about risk; (iii) how individuals want to take action on climate change but not move house. We will first describe these paradoxes leaned on our research's results and literature. After, we will discuss how these paradoxes can be reinterpreted in light of our theoretical proposal. We focus on the inhabitants of exposed coastal municipalities in France. Interviews and questionnaires were conducted and qualitative and quantitative data analyses were used (for more details, see:

[AQ2]for anonymity, the references will be added after the reviewing process).

Description of three commonly perceived paradoxes

Aware but not worried

When coastal inhabitants talk about risk as a whole in their municipality, most of them do not class coastal risks as the most important. Respondents evoke most often 'low concern' or 'no risk', or risks of daily life (road traffic, etc.) or environmental risks. In coastal municipalities, most emphasis is placed on risks related to seasonality effects (tourism and second-home growth) and gentrification, which threaten the municipality's regular economic activities and social diversity. A risk of devitalization, associated with population ageing, is also mentioned, along with agriculture-related pollution risks (nitrates, green algae, safe drinking water, etc.).

Inhabitants often cite regulation policies on urbanization as a risk because such policies restrict building permits. Indeed, it is not so much the fear of suffering damage from the sea that emerges, but that of being penalized by building permit restrictions, especially since 2010 in the wake of storm Xynthia 1 [START_REF] Krien | Place des risques côtiers dans les représentations sociales du cadre de vie d'habitants de communes littorales[END_REF]. When asked explicitly about coastal risks, inhabitants generally show a low level of concern (Michel-Guillou, Lalanne, & [START_REF] Michel-Guillou | Hommes et aléas: Appréhension des risques côtiers par des usagers et des gestionnaires de communes littorales[END_REF]. Erosion and sea flooding are usually experienced as occasional or exceptional, or put into perspective. They show a low level of perceived vulnerability to coastal risks and do not seem to be worried by them.

In this type of situation, the classic hypothesis is to think that these people are illinformed, unaware, in denial or uneducated (Boyer-Villemaire, Bernatchez, Benavente, & Cooper, 2014; [START_REF] Koutrakis | ICZM and coastal defence perception by beach users: Lessons from the Mediterranean coastal area[END_REF]. But yet almost all surveyed inhabitants acknowledge the existence of erosion and submersion phenomena. They talk about coastal processes and past damage, and in some municipalities, these phenomena have even been specially addressed and given media coverage. Through the widespread media coverage (internet, TV and the press) of climate change, people are becoming increasingly informed about coastal risks. Not being worried does not seem to be attributable to a lack of information.

And thus a paradox is created: many people are aware of and informed about coastal risks, but they are not worried about them.

Inhabitants cite risks but are strongly place attached

Nevertheless, our surveys found that some inhabitants spontaneously cited sea-related risks when talking about risks in general in their municipality. This percentage varies in time and space, but there is always a significant proportion of people who live near the sea and who have coastal risks in mind. This significant proportion can appear inconsistent, because to live in a place in which risks spontaneously come to mind might create cognitive dissonance [START_REF] Festinger | A theory of cognitive dissonance[END_REF], and therefore a feeling of uneasiness. However, in our surveys we did not find this problem of well-being.

On the contrary, the findings from all our surveys showed that almost all inhabitants are attached to the place they live in. They consider that living in a coastal community is primarily an advantage and even a 'privilege', owing to the beauty of the landscape, the view, the proximity of the beach and the sea, and the quality of life. Living here is an asserted choice.

These results are in line with the findings of many psychology studies showing that place attachment is an affective bond encouraging people to stay close to a place and to feel good there [START_REF] Hidalgo | Place attachment: Conceptual and empirical questions[END_REF][START_REF] Lewicka | Place attachment: How far have we come in the last 40 years[END_REF]. Place attachment contributes to enhancing people's identity insofar as the place with which they identify allows them to distinguish themselves from others (Twigger-Ross & Uzzell, 1996). An individual's living place thus contributes to maintaining or enhancing self-esteem and sense of self-efficacy (Wester-Herber, 2004). It is not surprising, therefore, that the inhabitants feel privileged to live in coastal locations, areas with strong place identities that allow people to positively differentiate their place from others. For [START_REF] Breakwell | Resisting representations and identity processes[END_REF], this distinctiveness is one of the principles on which identity is based. However, such place attachment hardly appears to be compatible with worrying about coastal risks. Indeed, many studies have shown that people who are emotionally close to the place in which they live tend to minimize risks of their daily life [START_REF] Billig | Is my home my castle? Place attachment, risk perception, and religious faith[END_REF][START_REF] Flanquart | An unwelcome user? Or how to negotiate the use of a risky space[END_REF][START_REF] Weiss | Entre connaissance, mémoire et oublis: Représentations de l'environnement et réactions face à une catastrophe naturelle[END_REF]. The more individuals are attached to a place, the more they feel safe and the less they perceive risk. Their representation of the place where they live allows them to be not particularly worried about coastal risks.

This brings us to our second paradox: inhabitants who spontaneously think about coastal risks feel privileged to live in that place.

Local willingness to take action but resisting change in adaptation strategies

As we have seen before, habitants are aware of the processes of erosion and sea flooding. For them, the risk is real today and will be reinforced in the future related to climate change. This awareness tends to reinforce their willingness to get involved in managing the risk.

Consequently, a majority of inhabitants believe that doing nothing is a poor option. Most inhabitants think that coping strategies must be put in place 'to combat' coastal risk. But there is a disparity between inhabitants' outlook and the French national coastline management strategy. Here two ways of social logic or rationality are opposed. The inhabitants are driven by a short-term and local perspective, linked to welfare and coastal place attachment. On the contrary, the government, which promotes the French national coastline management strategy, is driven by a long-term and global perspective of reduction of vulnerability and adaptation to climate change. And hence, the latter promotes relocation whereas the inhabitants prefer to resist and hold the line with 'hard' defences (Michel-Guillou & Meur-Ferec, 2016a).

Moreover, most inhabitants believe that protection should be mostly provided by public authorities. According to this willingness to stay, most people have a clear stance against the 'rolling-back process' or 'managed retreat' adaptation strategies (Michel-Guillou & Meur-Ferec, 2016a). In all interviews, inhabitants never evoked relocation as a preferred strategy.

Thus, while recognizing the overall importance of taking action and in particular adapting to climate change, most inhabitants prefer to defend their living place close to the sea.

Research on coastal risk shows that generally the risk of submersion or erosion is known to inhabitants, especially because it is identified in prevention documents, urban planning rules. But what is more 'worrying' to inhabitants is not the phenomena of submersion (or erosion) in themselves, but the fear of their consequences in terms of townplanning constraints (non-buildable lands, ban of house extensions, etc.), poor insurance coverage and compensation for damages, or relocation projects [START_REF] Krien | Place des risques côtiers dans les représentations sociales du cadre de vie d'habitants de communes littorales[END_REF]<<t/s: link>>Mineo-Kleiner & Meur-Ferec, 2016). Thus, coastal hazards (erosion and submersion), in terms of risk or threat, do not reach the inhabitants in their identity.

They are not or little worried about it. On the other hand, the constraints of town planning, the fear of being relocated, may reach them in their identity because these people feel privileged to live in a valued place ([AQ3]Michel-Guillou & Meur-Ferec, 2016).

According to [START_REF] Breakwell | Resisting representations and identity processes[END_REF] and [START_REF] Duveen | Representations, identities, resistance[END_REF], resistance can be seen to be one strategy to defend its identity, when individuals' beliefs, values and ideas are threatened. In this sense, the construction or reconstruction of social representations protect and maintain beliefs and values in the face of external threats. In our case, one coping strategy is, for example, 'not to move house', 'refuse relocation'; another is the construction of positive representations of a risk-free place [START_REF] Krien | Préservation d'une image positive de soi dans un cadre de vie "à risque[END_REF]. Thus, individuals construct social representations to defend themselves against the novelties. Here, the concept of place attachment (e.g., [START_REF] Hidalgo | Place attachment: Conceptual and empirical questions[END_REF], and more globally that of sense of place (e.g., [START_REF] Jorgensen | A comparative analysis of predictors of sense of place dimensions: Attachment to, dependence on, and identification with lakeshore properties[END_REF], is very relevant.

Discussion and conclusion

Explanation of these three paradoxes

Inhabitants who are informed but not worried may seem to be in denial of the risk. However, from our theoretical perspective, we argue that there is no denial: inhabitants know and recognize the physical process of erosion and sea flooding but they do not consider it as a threat (they are not worried), so there is no denial process ([AQ4]Baumeister, Dale, & Sommer, 1998).

In fact, coastal dynamics, including erosion and storm surges, are not spontaneously cited by the majority of inhabitants as risks. Sea hazards are elements that people have chosen to live with, without thinking about them daily in terms of risk. A process of objectification [START_REF] Moscovici | La psychanalyse, son image et son public[END_REF][START_REF] Moscovici | Why a theory of social representations[END_REF]) is at play. For inhabitants, the definition of submersion is an extreme event, when water levels rise to roof levels, like a tsunami. This representation has been derived from media images/information. Their personal experience of coastal risks does not include this kind of extreme event. So, by an objectification process, coastal risk has become 'flood' or 'wet feet', the storm a 'strong gust of wind' or a 'scene', etc. [START_REF] Bousquet | La tempête, du moment de nature au spectacle de société[END_REF]. It is not represented as a serious danger, not a 'submersion'. In that sense, many inhabitants do not mention coastal risks (erosion/submersion) at their local level. Such risks are situated outside of their places of residence. Risks are also shifted to a time scale beyond the inhabitants' lifetimes. In the same vein, people might consider that rising sea levels are important at the global level, but they do not necessarily have an effect at the local level. This distancing from risk may contribute to increased feelings of well-being insofar as it places the dangerous phenomenon further away, thus making it an abstraction [START_REF] Trope | Construal Level Theory of Psychological Distance[END_REF].

In consequence, coastal risks can be a concern for individuals without being perceived as an insurmountable problem. Studies on river flooding risks [START_REF] Bonaiuto | Flood risk, the role of neighbourhood attachment[END_REF][START_REF] Weiss | Les comportements de protection face au risque naturel: De la résistance à l'engagement[END_REF] have found that when people recognize the existence of erosion and submersion, this gives them a sense of control. In the same way, [START_REF] Luis | Is it all about awareness? The normalization of coastal risk[END_REF] found that awareness of coastal processes reinforces reliance on preventive protective measures -that is, people believe the risk can be managed. Knowledge of environmental processes combined with a sense of control allows individuals to maintain a positive place identity in a risky environment.

Furthermore, living near the sea is seen primarily as an advantage, and even a privilege, defined by the beauty of the landscape, the view, access to sea-related leisure and quality of life. The literature confirms this positive image of the coastline and its attractiveness in contemporary Western societies [START_REF] Kelly | Non-permanent residents, place attachment and "sea change" communities[END_REF]. This 'coast desire' [START_REF] Corbin | Le territoire du vide[END_REF] results in elevated property prices. However, the sea is the driving force of coastal hazards too [START_REF] Meur-Ferec | De la dynamique naturelle à la gestion intégrée de l'espace littoral[END_REF], responsible for flooding and coastal erosion (IPCC, 2013). Among considerations of risks in general, coastal risks are very specific because the hazard vector -the sea -is also an amenity. Taking this ambivalence into account helps to explain why people can be sensitive to coastal risks but simultaneously feel that it is a privilege to live close to the sea.

Their preference for holding the line [START_REF] Costa | Why do we decide to live with risk at the coast?[END_REF][START_REF] Friesinger | Perceptions of Gulf of St Lawrence coastal communities confronting environmental changes: Hazards and adaptation, Québec, Canada[END_REF][START_REF] Roca | Public perceptions of managed realignment strategies: The case study of the Ebro Delta in the Mediterranean basin[END_REF] is in accordance with their strong place attachment. This desire to control coastal erosion, reinforce sea defences and maintain what already exists can be linked to the identity dimension of place attachment. Thus, adaptation strategies are accepted as long as they do not lead to stigmatizing changes to the environment or a forced relocation (Wester-Herber, 2004) and, therefore, do not interfere with place identity [START_REF] Twigger-Ross | Place and identity processes[END_REF]. Otherwise, a resistance process takes place. Knowledge of representations can help to understand these 'resistance to change' expressed at the local level. Various forms of resistance lead to individuals generally approving of national measures while at the same time highlighting the impossibility of their local application [START_REF] Castro | Le développement durable et l'innovation législative: De la construction des idées à la compréhension des pratiques[END_REF].

Beyond this psychological place attachment, political and historical factors linked to the French tradition of a centralized and welfare state contribute to explaining the 'hold the line' position adopted by inhabitants [START_REF] André | Contribution of insurance data to cost assessment of coastal flood damage to residential buildings: Insights gained from Johanna 2008 and Xynthia 2010 storm events[END_REF][START_REF] Deboudt | Towards coastal risk management in France[END_REF] withdrawal. This new position of the government appears to be far removed from the position of most coastal residents, who are used to being supported by public funds to protect their private property. So, all these explanatory factors help with understanding the difficulties to implement some public policies at the local level.

The appeal of an interdisciplinary approach

To sum up, coastal inhabitants have a mixed position, based on cognitive, affective and behavioural dimensions, when it comes to coastal risks: they have knowledge of the hazards of erosion and sea flooding (cognitive dimension) but feel privileged to live near the sea (affective dimension). In terms of adaptation preferences, their strong trend to hold the line (behavioural dimension) is far from the recent French strategy in favour of relocation. This paper proposes another approach to a better understanding of the stances adopted by inhabitants of at-risk areas. They show the links between the representations of coastal risks, place attachment/place identity and adaptation strategy preferences.

Our approach is nourished by interdisciplinary [AQ5]research combining social psychology and coastal geography. A crossed perspective of these two disciplines throws another light on what is often interpreted as paradoxes and allows going beyond bias and denial. Figure 2 provides a summary of this approach.

Moreover, this interdisciplinary approach seems to be a relevant contribution towards the sustainable management of coastal risks. Knowledge about residents' representations can shed light on the difficulties in connecting global and local scales.

What can appear clear and rational from a theoretical and deterritorialized point of view (stopping coastal construction and rolling back the most exposed buildings) may be difficult to implement when faced with residents' positions and place attachment (purchasing and constructing houses along the coastline). As long as living at the seaside remains attractive and something that is socially and economically valued, then it seems very difficult to implement a relocation strategy.

Figure 1 .

 1 Figure 1. Systemic vulnerability model.

Figure 2 .

 2 Figure2. A psycho-geographical approach to go beyond bias and denial to analyse coastal

  embargo, este Número Especial es diferente: no habrá traducción al español de este artículo. Por favor, consulte la Introducción a este número [URL/DOI] para obtener más información sobre este cambio, que solo afectará a este número. Todos los artículos futuros continuarán publicándose en formato bilingüe. Title, abstract and keywords translated into Spanish by: / Título, resumen y palabras clave traducidos al castellano por: Miguel del Río Authors' Address / Correspondencia con las autoras: Elisabeth Guillou, Environmental Psychologist, LP3C EA 1285, Université de Bretagne Occidentale, Institut des Sciences de l'Homme et de la Société, Faculté des Lettres, 20, rue Duquesne, CS93837, 29 238 Brest

  . In fact, in France, victims of natural disasters benefit from a system of public compensation founded on national solidarity. Undoubtedly, this strong government interventionism to repair damage and compensate owners tends to reinforce individuals' sense of control and willingness to hold the line. Nowadays, however, in a context of public funds shortages and rising sea levels, and after the catastrophic event of Xynthia in 2010, the French government advocates the relocation inland of most exposed property(André, Boulet, Rey-

Valette,

[START_REF] André | Protection by hard defence structures or relocation of assets exposed to coastal risks: Contributions and drawbacks of cost-benefit analysis for long-term adaptation choices to climate change[END_REF][START_REF] Medde | Stratégie nationale de gestion intégrée du trait de côte. Vers la relocalisation des activités et des biens[END_REF][START_REF] Meur-Ferec | Plonevez-les-Flots: An imaginary territory to highlight the dilemmas confronting local officials when managing coastal risks[END_REF] <<t/s: link>>Mineo-Kleiner & Meur-Ferec, 2016)

. The welfare state is showing a gradual

Acknowledgements

This work was supported by two main research programmes, Cocorisco (ANR 2010-CEPL) 'Knowledge, understanding and management of coastal risks' and Miseeva (ANR 2007-VMC) 'Marine Inundation hazard exposure modelling and Social, Economic and Environmental Vulnerability Assessment in regard to global changes', both of which received support from the French National Research Agency (ANR). The authors would like to thank all project participants and L. David for the figures.

Note

1. In France, the storm surge Xynthia caused more than 30 deaths from flooding in 2010.

This was a dramatic [AQ].

Disclosure statement[AQ7]

No potential conflict of interest was reported by the authors.