title: Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation.
abstract: Reproduction is controlled in the brain by a neural network that drives the secretion of gonadotropin-releasing hormone (GnRH). Various permissive homeostatic signals must be integrated to achieve ovulation in mammals. However, the neural events controlling the timely activation of GnRH neurons are not completely understood. Here we show that kisspeptin, a potent activator of GnRH neuronal activity, directly communicates with neurons that synthesize the gaseous transmitter nitric oxide (NO) in the preoptic region to coordinate the progression of the ovarian cycle. Using a transgenic Gpr54-null IRES-LacZ knock-in mouse model, we demonstrate that neurons containing neuronal NO synthase (nNOS), which are morphologically associated with kisspeptin fibers, express the kisspeptin receptor GPR54 in the preoptic region, but not in the tuberal region of the hypothalamus. The activation of kisspeptin signaling in preoptic neurons promotes the activation of nNOS through its phosphorylation on serine 1412 via the AKT pathway and mimics the positive feedback effects of estrogens. Finally, we show that while NO release restrains the reproductive axis at stages of the ovarian cycle during which estrogens exert their inhibitory feedback, it is required for the kisspeptin-dependent preovulatory activation of GnRH neurons. Thus, interactions between kisspeptin and nNOS neurons may play a central role in regulating the hypothalamic-pituitary-gonadal axis in vivo.
authors.affiliation: Inserm, Jean-Pierre Aubert Research Center, U837, Development and Plasticity of the Postnatal Brain, Institut Fédératif de Recherche 114, France.
authors.forename: Naresh Kumar
authors.initials: NK
authors.lastname: Hanchate
authors.forename: Jyoti
authors.initials: J
authors.lastname: Parkash
authors.forename: Nicole
authors.initials: N
authors.lastname: Bellefontaine
authors.forename: Danièle
authors.initials: D
authors.lastname: Mazur
authors.forename: William H
authors.initials: WH
authors.lastname: Colledge
authors.forename: Xavier
authors.initials: X
authors.lastname: d'Anglemont de Tassigny
authors.forename: Vincent
authors.initials: V
authors.lastname: Prevot
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D030762:Estrous Cycle / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology* / Q000187:drug effects; D059648:Kisspeptins / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000378:metabolism*; D010060:Ovulation / Q000187:drug effects / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013256:Steroids / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C106628:KISS1 protein, human; C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D013256:Steroids; D007986:Luteinizing Hormone; D052248:Nitric Oxide Synthase Type I