Origin and Evolution of the Neuroendocrine Control of Reproduction in Vertebrates, With Special Focus on Genome and Gene Duplications.

In humans, 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-hypophysial portal blood system and stimulates the production of pituitary glycoprotein hormones, the two gonadotropins luteinizing hormone and follicle-stimulating hormone. A novel actor, the neuropeptide kisspeptin, acting upstream of GnRH, has attracted increasing attention in recent years. Other neuropeptides, such as gonadotropin-inhibiting hormone/RF-amide related peptide, and other members of the RF-amide peptide superfamily, as well as various nonpeptidic 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, and followed by paralogous gene loss or conservation, might have shaped the evolutionary scenarios of current families of key actors of the gonadotropic axis.

Urp1 and Urp2 act redundantly to maintain spine shape in zebrafish larvae.

Urp1 and Urp2 are two neuropeptides, members of the Urotensin 2 family, that have been recently involved in the control of body axis morphogenesis in zebrafish. They are produced by a population of sensory spinal neurons, called cerebrospinal fluid contacting neurons (CSF-cNs), under the control of signals relying on the Reissner fiber, an extracellular thread bathing in the CSF. Here, we have investigated further the function of Urp1 and Urp2 (Urp1/2) in body axis formation and maintenance. We showed that urp1;urp2 double mutants develop strong body axis defects during larval growth, revealing the redundancy between the two neuropeptides. These defects were similar to those previously reported in uts2r3 mutants. We observed that this phenotype is not associated with congenital defects in vertebrae formation, but by using specific inhibitors, we found that, at least in the embryo, the action of Urp1/2 signaling depends on myosin II contraction. Finally, we provide evidence that while the Urp1/2 signaling is functioning during larval growth, it is dispensable for embryonic development. Taken together, our results show that Urp1/2 signaling is required in larvae to promote correct vertebral body axis, most likely by regulating muscle tone.

The caudal neurosecretory system: a still enigmatic second neuroendocrine complex in fish.

The caudal neurosecretory system (CNSS) is a neuroendocrine complex, whose existence is specific to fishes. In teleosts, it consists of neurosecretory cells (Dahlgren cells) whose fibers are associated with a neurohemal terminal tissue (urophysis). In other actinopterygians as well as in chondrichthyes, the system is devoid of urophysis, so that Dahlgren cells end in a diffuse neurohemal region. Structurally, it has many similarities with the hypothalamic-neurohypophysial system. However, it differs regarding its position at the caudal end of the spinal cord and the nature of the hormones it secretes, the most notable ones being urotensins. The CNSS was first described more than 60 years ago, but its embryological origin is still hypothetical, and its role is poorly understood. Observations and experimental data gave some evidences of a possible involvement in osmoregulation, stress and reproduction. But one may question the benefit for fish to possess this second neurosecretory system, while the central hypothalamic-pituitary complex already controls such functions. As an introduction of our review, a brief report on the discovery of the CNSS is given. A description of its organization follows, and our review then focuses on the neuroendocrinology of the CNSS with the different factors it produces and secretes. The current knowledge on the ontogenesis and developmental origin of the CNSS is also reported, as well as its evolution. A special focus is finally given on what is known on its potential physiological roles.

Cerebrospinal Fluid-Contacting Neurons Sense pH Changes and Motion in the Hypothalamus.

CSF-contacting (CSF-c) cells are present in the walls of the brain ventricles and the central canal of the spinal cord and found throughout the vertebrate phylum. We recently identified ciliated somatostatin-/GABA-expressing CSF-c neurons in the lamprey spinal cord that act as pH sensors as well as mechanoreceptors. In the same neuron, acidic and alkaline responses are mediated through ASIC3-like and PKD2L1 channels, respectively. Here, we investigate the functional properties of the ciliated somatostatin-/GABA-positive CSF-c neurons in the hypothalamus by performing whole-cell recordings in hypothalamic slices. Depolarizing current pulses readily evoked action potentials, but hypothalamic CSF-c neurons had no or a very low level of spontaneous activity at pH 7.4. They responded, however, with membrane potential depolarization and trains of action potentials to small deviations in pH in both the acidic and alkaline direction. Like in spinal CSF-c neurons, the acidic response in hypothalamic cells is mediated via ASIC3-like channels. In contrast, the alkaline response appears to depend on connexin hemichannels, not on PKD2L1 channels. We also show that hypothalamic CSF-c neurons respond to mechanical stimulation induced by fluid movements along the wall of the third ventricle, a response mediated via ASIC3-like channels. The hypothalamic CSF-c neurons extend their processes dorsally, ventrally, and laterally, but as yet, the effects exerted on hypothalamic circuits are unknown. With similar neurons being present in rodents, the pH- and mechanosensing ability of hypothalamic CSF-c neurons is most likely conserved throughout vertebrate phylogeny.SIGNIFICANCE STATEMENT CSF-contacting neurons are present in all vertebrates and are located mainly in the hypothalamic area and the spinal cord. Here, we report that the somatostatin-/GABA-expressing CSF-c neurons in the lamprey hypothalamus sense bidirectional deviations in the extracellular pH and do so via different molecular mechanisms. They also serve as mechanoreceptors. The hypothalamic CSF-c neurons have extensive axonal ramifications and may decrease the level of motor activity via release of somatostatin. In conclusion, hypothalamic somatostatin-/GABA-expressing CSF-c neurons, as well as their spinal counterpart, represent a novel homeostatic mechanism designed to sense any deviation from physiological pH and thus constitute a feedback regulatory system intrinsic to the CNS, possibly serving a protective role from damage caused by changes in pH.

Revisiting the evolution of the somatostatin family: Already five genes in the gnathostome ancestor.

The somatostatin (SST) family members are a group of neuropeptides that are best known for their role in the regulation of growth, development and metabolism. The occurrence of six paralogous SST genes named SST1, SST2, SST3, SST4, SST5 and SST6 has been reported in vertebrates. It has been proposed that SST1, SST2 and SST5 arose in 2R from a common ancestral gene. SST3 and SST6 would have been subsequently generated by tandem duplications of the SST1 and SST2 genes respectively, at the base of the actinopterygian lineage. SST4 is thought to have appeared more recently from SST1, in teleost-specific 3R. In order to gain more insights into the SST gene family in vertebrates, we sought to identify which paralogs of this family are present in cartilaginous fish. For this purpose, we first searched the recently available genome and transcriptome databases from the catshark Scyliorhinus canicula. In a previous study, three S. canicula SST genes, called at that time SSTa, SSTb and SSTc, were identified and proposed to correspond to SST1, SST5 and SST2 respectively. In the present work, two additional SST genes, called SSTd and SSTe, were found in S. canicula plus two other chondrichtyan species, elephant shark (Callorhinchus milii) and whale shark (Rhincodon typus). Phylogeny and synteny analyses were then carried out in order to reveal the evolutionary relationships of SSTd and SSTe with other vertbrates SSTs. We showed that SSTd and SSTe correspond to SST2 and SST3 respectively, while SSTc corresponds to SST6 and not to SST2 as initially proposed. Our investigations in other vertebrate species also led us to find that the so-called SST2 gene in chicken, lungfish, sturgeons and teleosts actually corresponds to SST6. Conversely, the so-called SST6 gene in actinopterygians corresponds to SST2. Taken together, our results suggest that: i) SST3 and SST6 were already present in the gnathostome ancestor, much earlier than previously thought; ii) SST6 was also present in the tetrapod ancestor and still occurs in living birds; with this respect, it is likely that SST6 was independently lost several times during evolution: in amphibians, squamates and mammals; iii) SST2, SST3 and SST5 were probably lost in euteleosts, sarcopterygians and tetrapods, respectively.

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function.

Urotensin II (UII) is a cyclic neuropeptide that was first isolated from the urophysis of teleost fish on the basis of its ability to contract the hindgut. Subsequently, UII was characterized in tetrapods including humans. Phylogenetic studies and synteny analysis indicate that UII and its paralogous peptide urotensin II-related peptide (URP) belong to the somatostatin/cortistatin superfamily. In mammals, the UII and URP genes are primarily expressed in cholinergic neurons of the brainstem and spinal cord. UII and URP mRNAs are also present in various organs notably in the cardiovascular, renal, and endocrine systems. UII and URP activate a common G protein-coupled receptor, called UT, that exhibits relatively high sequence identity with somatostatin, opioid, and galanin receptors. The UT gene is widely expressed in the central nervous system (CNS) and in peripheral tissues including the retina, heart, vascular bed, lung, kidney, adrenal medulla, and skeletal muscle. Structure-activity relationship studies and NMR conformational analysis have led to the rational design of a number of peptidic and nonpeptidic UT agonists and antagonists. Consistent with the wide distribution of UT, UII has now been shown to exert a large array of biologic activities, in particular in the CNS, the cardiovascular system, and the kidney. Here, we review the current knowledge concerning the pleiotropic actions of UII and discusses the possible use of antagonists for future therapeutic applications.

Identification of three somatostatin genes in lampreys.

Somatostatins (SSs) are a structurally diverse family of neuropeptides that play important roles in the regulation of growth, development and metabolism in vertebrates. It has been recently proposed that the common ancestor of gnathostomes possessed three SS genes, namely SS1, SS2 and SS5. SS1 and SS2 are still present in most extant gnathostome species investigated so far while SS5 primarily occurs in chondrichthyes, actinopterygians and actinistia but not in tetrapods. Very little is known about the repertoire of SSs in cyclostomes, which are extant jawless vertebrates. In the present study, we report the cloning of the cDNAs encoding three distinct lamprey SS variants that we call SSa, SSb and SSc. SSa and SSb correspond to the two SS variants previously characterized in lamprey, while SSc appears to be a totally novel one. SSa exhibits the same sequence as gnathostome SS1. SSb differs from SSa by only one substitution (Thr12→Ser). SSc exhibits a totally unique structure (ANCRMFYWKTMAAC) that shares only 50% identity with SSa and SSb. SSa, SSb and SSc precursors do not exhibit any appreciable sequence similarity outside the C-terminal region containing the SS sequence. Phylogenetic analyses failed to clearly assign orthology relationships between lamprey and gnathostome SS genes. Synteny analysis suggests that the SSc gene arose before the split of the three gnathostome genes SS1, SS2 and SS5.

Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis.

OBJECTIVE: To define the role that repeat expansions of a GGGGCC hexanucleotide sequence of the C9orf72 gene play in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A genetic model for ALS was developed to determine whether loss of function of the zebrafish orthologue of C9orf72 (zC9orf72) leads to abnormalities in neuronal development. METHODS: C9orf72 mRNA levels were quantified in brain and lymphoblasts derived from FTLD and ALS/FTLD patients and in zebrafish. Knockdown of the zC9orf72 was performed using 2 specific antisense morpholino oligonucleotides to block transcription. Quantifications of spontaneous swimming and tactile escape response, as well as measurements of axonal projections from the spinal cord, were performed. RESULTS: Significantly decreased expression of C9orf72 transcripts in brain and lymphoblasts was found in sporadic FTLD and ALS/FTLD patients with normal-size or expanded hexanucleotide repeats. The zC9orf72 is selectively expressed in the developing nervous system at developmental stages. Loss of function of the zC9orf72 transcripts causes both behavioral and cellular deficits related to locomotion without major morphological abnormalities. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. INTERPRETATION: Our results indicate C9orf72 haploinsufficiency could be a contributing factor in the spectrum of ALS/FTLD neurodegenerative disorders. Loss of function of the zebrafish orthologue of zC9orf72 expression in zebrafish is associated with axonal degeneration of motor neurons that can be rescued by expressing human C9orf72 mRNA, highlighting the specificity of the induced phenotype. These results reveal a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease.

Evolution of the gastrin-cholecystokinin gene family revealed by synteny analysis.

Gastrin (GAST) and cholecystokinin (CCK) are two structurally and functionally related peptide hormones that exert many functions, including regulation of gastric and pancreatic secretion, feeding behaviour and energy homeostasis. GAST and CCK genes are assumed to have diverged from a common ancestral gene, over 500 million years ago in the vertebrate lineage. However, although a large number of GAST and CCK-related sequences have been identified both in vertebrate and non-vertebrate species, the evolutionary history of the GAST/CCK family remains little understood. To address this issue, we used extensive genome synteny comparisons of vertebrate chromosomes, in particular to evaluate the impact of whole-genome duplications. In the present study, we confirm that the GAST/CCK family in vertebrates is composed of two paralogous genes, namely GAST and CCK, and even three in teleosts, namely GAST, CCK1 and CCK2. We also show that the GAST and CCK genes arose by duplications of a single ancestral gene through the 2R and that the two copies of the CCK gene found in teleosts have probably been generated through the 3R. Finally, our results suggest that the vertebrate ancestor possessed four members of the GAST/CCK family, of which two have likely been lost during evolution.

Molecular cloning of the cDNAs encoding three somatostatin variants in the dogfish (Scylorhinus canicula).

It has been recently shown that the somatostatin gene family was likely composed of at least three paralogous genes in the common ancestor of all extant jawed vertebrates. These three genes, namely SS1, SS2 and SS5, are thought to have been generated through the two rounds of whole-genome duplications (2R) that took place early during the vertebrate evolution. In the present study, we report the cloning of three distinct somatostatin cDNAs from the dogfish Scylorhinus canicula, a member of the group of cartilaginous fish. We decided to call these cDNAs, at least provisionally, SSa, SSb and SSc, respectively. Two of them, SSa and SSb, encode proteins that both contain the same tetradecapeptide sequence at their C-terminal extremity (AGCKNFFWKTFTSC). This putative peptide is identical to that generated by the SS1 gene in other vertebrate species. The last cDNA, SSc, encodes a protein that contains at its C-terminal extremity the same peptide sequence as that generated by the SS2 gene in teleosts (APCKNFFWKTFTSC). Phylogenetic analysis showed that the SSa and SSc genes likely correspond to the dogfish counterparts of the SS1 and SS2 genes, respectively. In contrast, the phylogenetic status of the SSb gene is less clear. Several lines of evidence suggest that it could correspond to the SS5 gene, but this view will need to be confirmed, for example by synteny analysis. Finally, RT-PCR analysis revealed that SSa, SSb and SSc genes are differentially expressed in dogfish tissues, suggesting that the corresponding peptides may exert distinct functions.

Impact of gene/genome duplications on the evolution of the urotensin II and somatostatin families.

The present review describes the molecular evolution of two phylogenetically related families of neuropeptides, the urotensin II (UII) and somatatostatin (SS) families. The UII family consists of four paralogous genes called UII, URP, URP1 and URP2 and the SS family is composed of six paralogous genes named SS1, SS2, SS3, SS4, SS5 and SS6. All these paralogs are present in teleosts, while only four of them, UII, URP, SS1 and SS2 are detected in tetrapods. Comparative genomics showed that most of these genes, namely UII, URP, URP1 and URP2 on the one hand and SS1, SS2 and SS5 on the other hand arose through the 2R. In contrast, the teleost-specific 3R had a much more moderate impact since it only concerned the UII and SS1 genes, which once duplicated, generated a second UII copy and SS4, respectively. The two remaining genes, SS3 and SS6, arose through tandem duplications of the SS1 and SS2 genes respectively, probably in the stem lineage of actinopterygians, before the emergence of teleosts. The history of the UII and SS families has also been marked by massive gene lost, both in tetrapods and in teleosts, but only after the 3R in this latter lineage. Finally, ancestral UII and SS genes are thought to have arisen through tandem duplication of a single ancestral gene, largely before the 1R. An important challenge for the future will be to understand the physiological significance of the molecular diversity of these two families.

Characterization of the true ortholog of the urotensin II-related peptide (URP) gene in teleosts.

It has been recently established that the urotensin II (UII) family consists of four distinct paralogs in bony vertebrates, namely UII, and the three UII-related peptides (URPs) called URP, URP1 and URP2. These four peptides are encoded by genes which arose from the two rounds of tetraploidization (2R) which took place early during vertebrate evolution. Up to now, three of them, UII, URP1 and URP2, have been identified in teleosts, while only two, UII and URP, have been reported in tetrapods. The fact that fish URP has not been found in previous studies led to the suggestion that the corresponding gene had been lost in the teleost lineage. In the present study, we show that this view is not correct. A search of the most recent release of the Ensembl genome database led us to identify a novel UII/URP-like gene in teleosts. Using synteny analysis, we demonstrate that this gene corresponds to the true ortholog of the tetrapod URP gene. Molecular cloning of the corresponding cDNA in medaka revealed that URP gene encodes a putative peptide, with the primary structure GEPCFWKYCV. In stickleback, tilapia and takifugu, URP exhibited the same sequence while, in tetraodon, it differed by only one amino acid substitution Gly ↔ Ser. In zebrafish, URP appeared totally divergent at its N-terminus with the structure DDTCFWKYCV. In conclusion, the occurrence of a true URP in teleosts shows that the quartet of UII-related genes which arose from 2R has been integrally preserved in this lineage.

[The caudal neurosecretory system, the other "neurohypophysial" system in fish]. / Le système neurosécréteur caudal, l'autre système « neurohypophysaire ¼ des poissons.

The caudal neurosecretory system (CNSS) is a neuroendocrine complex whose existence is specific to fishes. Structurally, it has many similarities with the hypothalamic-neurohypophyseal complex of other vertebrates. However, it differs regarding its position at the caudal end of the spinal cord and the nature of the hormones it secretes, the most important being urotensins. The CNSS was first described more than 60 years ago, but its embryological origin is totally unknown and its role is still poorly understood. Paradoxically, it is almost no longer studied today. Recent developments in imaging and genome editing could make it possible to resume investigations on CNSS in order to solve the mysteries that still surround it.

Title: Le système neurosécréteur caudal, l'autre système « neurohypophysaire ¼ des poissons. Abstract: Le système neurosécréteur caudal (SNSC) est un complexe neuroendocrinien propre aux poissons. Sur le plan structural, il présente de nombreuses similitudes avec le complexe hypothalamo-neurohypophysaire d'autres vertébrés. Il s'en distingue toutefois par sa position, à l'extrémité caudale de la moelle épinière, et par la nature des hormones qu'il sécrète, les plus importantes étant les urotensines. Le SNSC a été décrit pour la première fois il y a plus de 60 ans, mais son origine embryologique est totalement inconnue et son rôle reste mal compris. Paradoxalement, il n'est presque plus étudié aujourd'hui. Les développements récents en imagerie et en génie génétique pourraient justifier la reprise d'investigations sur le SNSC afin de lever les mystères qui continuent de l'entourer.

Evolution of the gonadotropin-releasing hormone (GnRH) gene family in relation to vertebrate tetraploidizations.

The neuropeptide gonadotropin-releasing hormone (GnRH) plays an important role in the control of reproductive functions. Vertebrates possess multiple GnRH isoforms that are classified into three main groups, namely GnRH1, GnRH2 and GnRH3. In the present study, we show that the chromosomal organization of the three GnRH loci is very well conserved among gnathostome species. We analyzed genes belonging to several other multigenic families that are present in the vicinity of GnRH genes. Five of them were seen to occur in four chromosomal regions that clearly form a paralogon. Moreover, we show that the homologous regions in the amphioxus genome are present on a single locus. Taken together, these observations indicate that GnRH1, GnRH2 and GnRH3 genes represent three paralogous genes that resulted from the two rounds of tetraploidization that took place early in vertebrate evolution. They confirm that the GnRH3 gene which is currently known only in teleost has most likely been lost in the tetrapod lineage. Finally, they suggest the existence of a fourth GnRH gene, named GnRH4. Whether the GnRH4 gene still exists in extant vertebrates is currently unknown. A search for this putative gene would be particularly useful in basal groups such as agnathans and cartilaginous fish.

Urotensin II-related peptide (Urp) is expressed in motoneurons in zebrafish, but is dispensable for locomotion in larva.

The urotensin 2 (uts2) gene family consists of four paralogs called uts2, uts2-related peptide (urp), urp1 and urp2. uts2 is known to exert a large array of biological effects, including osmoregulation, control of cardiovascular functions and regulation of endocrine activities. Lately, urp1 and urp2 have been shown to regulate axial straightening during embryogenesis. In contrast, much less is known about the roles of urp. The aim of the present study was to investigate the expression and the functions of urp by using the zebrafish as a model. For this purpose, we determined the expression pattern of the urp gene. We found that urp is expressed in motoneurons of the brainstem and the spinal cord, as in tetrapods. This was confirmed with a new Tg(urp:gfp) fluorescent reporter line. We also generated a urp knockout mutant by using CRISPR/Cas9-mediated genome editing and analysed its locomotor activity in larvae. urp mutant did not exhibit any apparent defect of spontaneous swimming when compared to wild-type. We also tested the idea that urp may represent an intermediary of urp1 and urp2 in their role on axial straightening. We found that the upward bending of the tail induced by the overexpression of urp2 in 24-hpf embryos was not altered in urp mutants. Our results indicate that urp does probably not act as a relay downstream of urp2. In conclusion, the present study showed that zebrafish urp gene is primarily expressed in motoneurons but is apparently dispensable for locomotor activity in the early larval stages.

Conserved role of the urotensin II receptor 4 signalling pathway to control body straightness in a tetrapod.

Urp1 and Urp2 are two neuropeptides of the urotensin II family identified in teleost fish and mainly expressed in cerebrospinal fluid (CSF)-contacting neurons. It has been recently proposed that Urp1 and Urp2 are required for correct axis formation and maintenance. Their action is thought to be mediated by the receptor Uts2r3, which is specifically expressed in dorsal somites. In support of this view, it has been demonstrated that the loss of uts2r3 results in severe scoliosis in adult zebrafish. In the present study, we report for the first time the occurrence of urp2, but not of urp1, in two tetrapod species of the Xenopus genus. In X. laevis, we show that urp2 mRNA-containing cells are CSF-contacting neurons. Furthermore, we identified utr4, the X. laevis counterparts of zebrafish uts2r3, and we demonstrate that, as in zebrafish, it is expressed in the dorsal somatic musculature. Finally, we reveal that, in X. laevis, the disruption of utr4 results in an abnormal curvature of the antero-posterior axis of the tadpoles. Taken together, our results suggest that the role of the Utr4 signalling pathway in the control of body straightness is an ancestral feature of bony vertebrates and not just a peculiarity of ray-finned fishes.

Differential expression of five prosomatostatin genes in the central nervous system of the catshark Scyliorhinus canicula.

Five prosomatostatin genes (PSST1, PSST2, PSST3, PSST5, and PSST6) have been recently identified in elasmobranchs (Tostivint et al., General and Comparative Endocrinology, 2019, 279, 139-147). In order to gain insight into the contribution of each somatostatin to specific nervous systems circuits and behaviors in this important jawed vertebrate group, we studied the distribution of neurons expressing PSST mRNAs in the central nervous system (CNS) of Scyliorhinus canicula using in situ hybridization. Additionally, we combined in situ hybridization with tyrosine hydroxylase (TH) immunochemistry for better characterization of PSST1 and PSST6 expressing populations. We observed differential expression of PSST1 and PSST6, which are the most widely expressed PSST transcripts, in cell populations of many CNS regions, including the pallium, subpallium, hypothalamus, diencephalon, optic tectum, midbrain tegmentum, and rhombencephalon. Interestingly, numerous small pallial neurons express PSST1 and PSST6, although in different populations judging from the colocalization of TH immunoreactivity and PSST6 expression but not with PSST1. We observed expression of PSST1 in cerebrospinal fluid-contacting (CSF-c) neurons of the hypothalamic paraventricular organ and the central canal of the spinal cord. Unlike PSST1 and PSST6, PSST2, and PSST3 are only expressed in cells of the hypothalamus and in some hindbrain lateral reticular neurons, and PSST5 in cells of the region of the entopeduncular nucleus. Comparative data of brain expression of PSST genes indicate that the somatostatinergic system of sharks is the most complex reported in any fish.

Selenoprotein T: An Essential Oxidoreductase Serving as a Guardian of Endoplasmic Reticulum Homeostasis.

Significance: Selenoproteins incorporate the essential nutrient selenium into their polypeptide chain. Seven members of this family reside in the endoplasmic reticulum (ER), the exact function of most of which is poorly understood. Especially, how ER-resident selenoproteins control the ER redox and ionic environment is largely unknown. Since alteration of ER function is observed in many diseases, the elucidation of the role of selenoproteins could enhance our understanding of the mechanisms involved in ER homeostasis. Recent Advances: Among selenoproteins, selenoprotein T (SELENOT) is remarkable as the most evolutionarily conserved and the only ER-resident selenoprotein whose gene knockout in mouse is lethal. Recent data indicate that SELENOT contributes to ER homeostasis: reduced expression of SELENOT in transgenic cell and animal models promotes accumulation of reactive oxygen and nitrogen species, depletion of calcium stores, activation of the unfolded protein response and impaired hormone secretion. Critical Issues: SELENOT is anchored to the ER membrane and associated with the oligosaccharyltransferase complex, suggesting that it regulates the early steps of N-glycosylation. Furthermore, it exerts a selenosulfide oxidoreductase activity carried by its thioredoxin-like domain. However, the physiological role of the redox activity of SELENOT is not fully understood. Likewise, the nature of its redox partners needs to be further characterized. Future Directions: Given the impact of ER stress in pathologies such as neurodegenerative, cardiovascular, metabolic and immune diseases, understanding the role of SELENOT and developing derived therapeutic tools such as selenopeptides to improve ER proteostasis and prevent ER stress could contribute to a better management of these diseases.

Somatostatin 1.1 contributes to the innate exploration of zebrafish larva.

Pharmacological experiments indicate that neuropeptides can effectively tune neuronal activity and modulate locomotor output patterns. However, their functions in shaping innate locomotion often remain elusive. For example, somatostatin has been previously shown to induce locomotion when injected in the brain ventricles but to inhibit fictive locomotion when bath-applied in the spinal cord in vitro. Here, we investigated the role of somatostatin in innate locomotion through a genetic approach by knocking out somatostatin 1.1 (sst1.1) in zebrafish. We automated and carefully analyzed the kinematics of locomotion over a hundred of thousand bouts from hundreds of mutant and control sibling larvae. We found that the deletion of sst1.1 did not impact acousto-vestibular escape responses but led to abnormal exploration. sst1.1 mutant larvae swam over larger distance, at higher speed and performed larger tail bends, indicating that Somatostatin 1.1 inhibits spontaneous locomotion. Altogether our study demonstrates that Somatostatin 1.1 innately contributes to slowing down spontaneous locomotion.

Characterization of urotensin II, distribution of urotensin II, urotensin II-related peptide and UT receptor mRNAs in mouse: evidence of urotensin II at the neuromuscular junction.

Urotensin II (UII) and UII-related peptide (URP) are paralog neuropeptides whose existence and distribution in mouse have not yet been investigated. In this study, we showed by HPLC/RIA analysis that the UII-immunoreactive molecule in the mouse brain corresponds to a new UII(17) isoform. Moreover, calcium mobilization assays indicated that UII(17) and URP were equally potent in stimulating UII receptor (UT receptor). Quantitative RT-PCR and in situ hybridization analysis revealed that in the CNS UII and URP mRNAs were predominantly expressed in brainstem and spinal motoneurons. Besides, they were differentially expressed in the medial vestibular nucleus, locus coeruleus and the ventral medulla. In periphery, both mRNAs were expressed in skeletal muscle, testis, vagina, stomach, and gall bladder, whereas only URP mRNA could be detected in the seminal vesicle, heart, colon, and thymus. By contrast, the UT receptor mRNA was widely expressed, and notably, very high amounts of transcript occurred in skeletal muscle and prostate. In the biceps femoris muscle, UII-like immunoreactivity was shown to coexist with synaptophysin in muscle motor end plate regions. Altogether these results suggest that (i) UII and URP may have many redundant biological effects, especially at the neuromuscular junction; (ii) URP may more specifically participate to autonomic, cardiovascular and reproductive functions.