Upon binding to specific, high-affinity receptors on gonadotrope cells of the anterior pituitary gland, gonadotropin-releasing hormone (GnRH) stimulates the synthesis of luteinizing hormone (LH) and follicle stimulating hormone (FSH) which are essential for normal gonadal function in both males and females. Therefore, the interaction of GnRH with its cognate pituitary receptor serves as a central point for regulation of reproductive function. To examine transcriptional regulation of the GnRH receptor (GnRH), we have cloned the gene encoding the murine GnRHR and found that expression of the GnRHR gene in gonadotrope- derived alphaT3-1 cells is mediated by a tripartite enhancer comprised of a steroidogenic factor-1 (SF-1) binding site, a consensus activator protein-1 (AP-1) element and a non-canonical element we have termed the GnRH receptor activating sequence (GRAS). Further, 1900 bp of proximal promoter is sufficient to confer tissue-specific expression and GnRH responsiveness in transgenic mice. Recently, we have determined that GnRH regulation of the GnRHR gene in alphaT3-1 cells is partially mediated by protein kinase C/extracellular signal-regulated kinase dependent activation of the canonical AP-1 site. We have also determined that members of both the fos and jun family of transcription factors bind at AP-1 in the GnRHR promoter. Further studies are, however, necessary to delineate the signal transduction cascade(s) and downstream targets that lead to activation of AP-1 by GnRH. Accordingly, we propose 3 specific aims to: 1) determine if dual MAP kinase signaling cascades are necessary for GnRH induction of the GnRHR gene promoter; 2) identify the protein(s) that ultimately mediate GnRHR transactivation at AP-1; and 3) determine if AP-1 is necessary for GnRH regulation of the GnRHR gene promoter in transgenic mice.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HD008558-01
Application #
6012451
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Vogel, Donna L
Project Start
1999-08-01
Project End
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523