title: Kisspeptin regulates gonadotropin genes via immediate early gene induction in pituitary gonadotropes.
abstract: Kisspeptin signaling through its receptor, Kiss1R, is crucial for many reproductive functions including puberty, sex steroid feedback, and overall fertility. Although the importance of Kiss1R in the brain is firmly established, its role in regulating reproduction at the level of the pituitary is not well understood. This study presents molecular analysis of the role of kisspeptin and Kiss1R signaling in the transcriptional regulation of the gonadotropin gene β-subunits, LHβ and FSHβ, using LβT2 gonadotrope cells and murine primary pituitary cells. We show that kisspeptin induces LHβ and FSHβ gene expression, and this induction is protein kinase C dependent and mediated by the immediate early genes, early growth response factor 1 and cFos, respectively. Additionally, kisspeptin induces transcription of the early growth response factor 1 and cFos promoters in LβT2 cells. Kisspeptin also increases gonadotropin gene expression in mouse primary pituitary cells in culture. Furthermore, we find that Kiss1r expression is enhanced in the pituitary of female mice during the estradiol-induced LH surge, a critical component of the reproductive cycle. Overall, our findings indicate that kisspeptin regulates gonadotropin gene expression through the activation of Kiss1R signaling through protein kinase C, inducing immediate early genes in vitro, and responds to physiologically relevant cues in vivo, suggesting that kisspeptin affects pituitary gene expression to regulate reproductive function.
authors.affiliation: Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Witham
authors.forename: Jason D
authors.initials: JD
authors.lastname: Meadows
authors.forename: Hanne M
authors.initials: HM
authors.lastname: Hoffmann
authors.forename: Shadi
authors.initials: S
authors.lastname: Shojaei
authors.forename: Djurdjica
authors.initials: D
authors.lastname: Coss
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kauffman
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D037201:Follicle Stimulating Hormone, beta Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early / Q000235:genetics; D052681:Gonadotrophs / Q000166:cytology / Q000378:metabolism*; D059648:Kisspeptins / Q000378:metabolism*; D037101:Luteinizing Hormone, beta Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D012098:Reproduction / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D037201:Follicle Stimulating Hormone, beta Subunit; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D037101:Luteinizing Hormone, beta Subunit; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018808:Transcription Factor AP-1; D011493:Protein Kinase C