title: Jak2 is necessary for neuroendocrine control of female reproduction.
abstract: Gonadotropin-releasing hormone (GnRH) neurons represent the final common output of signals from the brain that regulates reproductive function. A wide range of environmental factors impact GnRH neuron activity including disease, stress, nutrition, and seasonal cues, as well as gonadal steroid hormones. The CNS response is thought to be mediated, at least in part, through intermediate signaling molecules that affect GnRH neuronal activity. In vitro, GnRH neuronal cell lines respond to a variety of ligands that activate the Jak (Janus-activated kinase)/STAT (signal transducers and activators of transcription) intracellular signaling pathway. To determine its biological function in reproduction, we used Cre (cAMP response element)/LoxP technology to generate GnRH neuron-specific Jak2 conditional knock-out (Jak2 G(-/-)) mice. GnRH mRNA levels were reduced in Jak2 G(-/-) mice when compared with controls, while the number of GnRH neurons was equivalent, indicating a reduction in GnRH gene expression. Secretion of GnRH is also reduced as basal serum luteinizing hormone (LH) levels were significantly lower in female Jak2 G(-/-) mice while the pituitary responded normally to exogenous GnRH. Preovulatory LH surge levels were blunted in Jak2 G(-/-) mice, which was correlated with reduced GnRH neuronal activation as assessed by c-Fos. However, the activation of GnRH neurons following release from estrogen-negative feedback is retained. Female Jak2 G(-/-) mice exhibited significantly delayed puberty and first estrus, abnormal estrous cyclicity, and impaired fertility. These results demonstrate an essential role for Jak2 signaling in GnRH neurons for normal reproductive development and fertility in female mice.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. swu24@jhmi.edu
authors.forename: Sheng
authors.initials: S
authors.lastname: Wu
authors.forename: Sara
authors.initials: S
authors.lastname: Divall
authors.forename: Gloria E
authors.initials: GE
authors.lastname: Hoffman
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Le
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolfe
mesh_terms: D000818:Animals; D002452:Cell Count / Q000379:methods; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D030762:Estrous Cycle / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology; D053614:Janus Kinase 2 / Q000172:deficiency / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010052:Ovariectomy; D010053:Ovary / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011628:Puberty, Delayed / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2