title: Nuclear receptor LRH-1 induces the reproductive neuropeptide kisspeptin in the hypothalamus.
abstract: The differential expression and secretion of the neuropeptide kisspeptin from neurons in the arcuate (Arc) and anteroventral periventricular (AVPV) nuclei of the hypothalamus coordinate the temporal release of pituitary gonadotropins that control the female reproductive cycle. However, the molecular basis for this differential regulation is incompletely understood. Here, we report that liver receptor homolog-1 (LRH-1), a member of the nuclear receptor superfamily, is expressed in kisspeptin neurons in the Arc but not in the AVPV in female mice. LRH-1 binds directly to the kisspeptin (Kiss1) promoter and stimulates Kiss1 transcription. Deletion of LRH-1 from kisspeptin neurons in mice decreased Kiss1 expression in the Arc, leading to reduced plasma FSH levels, dysregulated follicle maturation, and prolongation of the estrous cycle. Conversely, overexpression of LRH-1 in kisspeptin neurons increased Arc Kiss1 expression and plasma FSH concentrations. These studies provide a molecular basis for the differential regulation of basal kisspeptin expression in Arc and AVPV neurons and reveal a prominent role for LRH-1 in hypothalamus in regulating the female reproductive axis.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Room ND9.124, Dallas, Texas 75390-9041, USA.
authors.forename: Stan D
authors.initials: SD
authors.lastname: Atkin
authors.forename: Bryn M
authors.initials: BM
authors.lastname: Owen
authors.forename: Angie L
authors.initials: AL
authors.lastname: Bookout
authors.forename: Roberta M
authors.initials: RM
authors.lastname: Cravo
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lee
authors.forename: Carol F
authors.initials: CF
authors.lastname: Elias
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012098:Reproduction
chemical_list: C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D009479:Neuropeptides; C431936:Nr5a2 protein, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear