Role of Sema3A/Neuropilin1 signaling in GnRH system development and study of the involvement of NO-synthesizing neurons in the kisspeptin-dependent preovulatory activation of adult GnRH neurons
Role de la voie de signalisation Sema3A/Neuropilin1 dans le développement du système à GnRH et étude de l'implication des neurones synthétisant le NO dans l'activation préovulatoire des neurones à GnRH adultes initiée par les neurones KISS
Résumé
Reproduction in mammals is regulated by neurons that synthesize and secrete gonadotropin-releasing hormone (GnRH) and across the species these neurons are present in few numbers scattered in the hypothalamus. Due to limited neurogenesis of these neuronal cell types outside the brain in the olfactory placode, these neurons are subjected to tight regulation during embryonic development to reach their final targets in the hypothalamus, from birth until puberty for minimal secretion of hormone and during adults to achieve pulsatile secretion of the hormone. Deregulation in any of these mechanisms may lead to deleterious effects on adult reproduction and clinical pathologies like absence of puberty, hypogonadism, sterility, amenorrhea, etc. Kallmann syndrome (KS), one of these severe reproductive pathologies is an inherited disorder and patients affected with this syndrome display anosmia (inability to smell) and hypogonadotropic hypogonadism (HH). Genetic screening of molecules in these patients lead to identification of genes like KAL1, FGFR1, FGF8, PROK2, PROKR2, WDR11 and CHD7 encoding proteins that play an important role in migration and targeting of olfactory system during embryonic development however these genes account only for 30% of KS cases emphasizing the need for further characterization and identification of other genes. While these proteins are involved in ontogenesis olfactory and GnRH system, genetic screening of molecules in patients suffering from normosmic idiopathic HH lead to identification of genes encoding for Kisspeptin receptor-GPR54, TAC-TACR3, LEP-LEPR, PCSK-1, GnRH receptor-GnRHR and GnRH-1 itself that play a crucial role in occurrence of puberty or adult reproduction. Here, for my PhD thesis, we focused on studying the role of guidance molecule Semaphorin3A (Sema3A)-Neuropilin1 (Nrp1) interactions in ontogenesis of GnRH neurons during embryonic development while in adults we first addressed the question if hypothalamic Kisspeptin neurons interact with neurons containing neuronal nitric oxide synthase (nNOS), the mutation of which causes HH in mice, and physiological significance of this interactions in regulation of GnRH neurons and neuroendocrine control of female reproduction. Finally our results demonstrate that Sema3A-Nrp1 interactions are implicated in ontogenesis of olfactory and GnRH neurons during embryonic development and nNOS neurons are important mediators of peripheral estrogens-kisspeptin signaling onto GnRH neurons and adult reproduction and propose to further study the implication of nNOS neurons in reproductive pathologies.
La reproduction dans des mammifères est réglée par les neurones qui synthétisent et sécrètent l'hormone de gonadotropin-sortie (GnRH) et à travers l'espèce ces neurones sont présents dans peu de nombres dispersés dans l'hypothalamus. En raison de limité neurogenesis de ceux des types cellulaires neuronaux à l'extérieur du cerveau dans placode olfactif, ces neurones sont soumis au règlement serré pendant le développement embryonnaire pour atteindre leurs objectifs finaux dans l'hypothalamus, de la naissance jusqu'à la puberté pour la sécrétion minimale d'hormone et pendant des adultes pour réaliser la sécrétion pulsatile de l'hormone. La dérégulation dans n'importe lequel de ces mécanismes peut mener aux effets délétères sur la reproduction adulte et des pathologies cliniques comme l'absence de puberté, hypogonadism, la stérilité, l'aménorrhée, etc. Kallmann syndrome (KS), un d'entre ceux sévères (graves) reproducteur
Domaines
Médecine humaine et pathologie
Origine : Version validée par le jury (STAR)