title: Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism.
abstract: Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, because kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown. The study described herein shows that the kisspeptin-Kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function. In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron-specific Kiss1r knockout mouse model (GKirKO) was generated, and reproductive development and phenotype were assessed. Both female and male GKirKO mice were infertile, having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice. Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.
authors.affiliation: Department of Pediatrics (H.J.N., M.L.S., A.W., S.R.), Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (G.H.), Morgan State University, Baltimore, Maryland 21251; School of Biological Sciences (Y.K.), Inje University, Gimhae, 621-749, South Korea; and University of Illinois at Champaign-Urbana (C.K.), Champaign, Illinois 61820.
authors.forename: Horacio J
authors.initials: HJ
authors.lastname: Novaira
authors.forename: Momodou L
authors.initials: ML
authors.lastname: Sonko
authors.forename: Gloria
authors.initials: G
authors.lastname: Hoffman
authors.forename: Yongbum
authors.initials: Y
authors.lastname: Koo
authors.forename: Chemyong
authors.initials: C
authors.lastname: Ko
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolfe
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
mesh_terms: D000818:Animals; D004967:Estrogens / Q000502:physiology; D030762:Estrous Cycle; D005260:Female; D052681:Gonadotrophs / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007006:Hypogonadism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D007246:Infertility / Q000235:genetics / Q000378:metabolism; D059648:Kisspeptins / Q000502:physiology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010053:Ovary / Q000002:abnormalities / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D015398:Signal Transduction; D013737:Testis / Q000002:abnormalities / Q000473:pathology
chemical_list: D004967:Estrogens; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone