title: Genetic mechanisms mediating kisspeptin regulation of GnRH gene expression.
abstract: Kisspeptins (Kiss) have been shown to be key components in the regulation of gonadotropin-releasing hormone (GnRH) secretion. In vitro studies have demonstrated an increase in GnRH gene expression by Kiss suggesting regulation of GnRH at both the secretory and pretranslational levels. Here, we define genetic mechanisms that mediate Kiss action on target gene expression. In vitro, sequential deletions of the mouse GnRH (mGnRH) gene promoter fused to the luciferase (LUC) reporter gene localized at kisspeptin-response element (KsRE) between -3446 and -2806 bp of the mGnRH gene. In vivo, transgenic mice bearing sequential deletions of the mGnRH gene promoter linked to the LUC reporter localized an identical KsRE. To define the mechanism of regulation, Kiss was first shown to induce nucleosome-depleted DNA within the KsRE, and a potential binding site for the transcription factor, Otx-2, was revealed. Furthermore, increased Otx-2 mRNA, protein, and binding to the KsRE after Kiss treatment were demonstrated. In conclusion, this work identified elements in GnRH-neuronal cell lines and in transgenic mice that mediate positive regulation of GnRH by Kiss. In addition, we show for the first time that Otx-2 is regulated by Kiss, and plays a role in mediating the transcriptional response of mGnRH gene.
authors.affiliation: Department of Pediatrics, Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Horacio J
authors.initials: HJ
authors.lastname: Novaira
authors.forename: Doris
authors.initials: D
authors.lastname: Fadoju
authors.forename: Daniel
authors.initials: D
authors.lastname: Diaczok
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D059648:Kisspeptins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects
chemical_list: D059648:Kisspeptins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D007987:Gonadotropin-Releasing Hormone