Appropriate tissue-specific expression of gonadotropin-releasing hormone (GnRH) is critical for reproductive competence. The extremely low levels of ovarian expression, along with the paucity and scattered distribution of GnRH neurons have limited the in vivo study of GnRH gene regulation. Recently, I generated transgenic mice using fragments of the mouse GnRH (mGnRH) gene promoter fused to the luciferase reporter gene. My preliminary findings suggest that a common element in the mGnRH promoter, between -2806 and -2078 bp, may mediate the differential regulation of hypothalamic and ovarian mGnRH gene expression. Oct-1 has been shown to bind to sequences in this mGnRH promoter region. The overall goal of this proposal is to examine the role Oct-1 may have on the regulation of hypothalamic and ovarian mGnRH gene expression in order to elucidate the molecular mechanisms involved in the differential regulation of GnRH gene expression. The studies propose to generate additional lines of transgenic mice to define elements in the mGnRH promoter that enhance hypothalamic GnRH gene expression and repress ovarian GnRH gene expression. These DNA elements will be characterized in vitro to identify factors that may differentially regulate mGnRH gene expression in the hypothalamus and ovary. To examine the role that Oct-1 may play in the hypothalamic expression of mGnRH, GnRH-specific Oct-1 knockout mice will be generated. This project will be performed by Dr. Helen H. Kim under the guidance of Dr. Sally Radovick in the Section of Pediatric Endocrinology at The University of Chicago. Dr. Helen Kim is a reproductive endocrinologist who is dedicated to pursuing an academic research career. With additional research training, she should develop the expertise needed to investigate female reproductive function at a molecular level. Dr. Radovick has an outstanding research record studying the molecular mechanisms underlying GnRH gene expression and has the necessary expertise to provide research training in molecular endocrinology. There are numerous resources available for the applicant, and the strong interactions among the research faculty in the Sections of Endocrinology in the Departments of Medicine and Pediatrics provide an ideal environment for both a didactic and technical education.
| Kim, Helen H; Wolfe, Andrew; Cohen, Ronald N et al. (2007) In vivo identification of a 107-base pair promoter element mediating neuron-specific expression of mouse gonadotropin-releasing hormone. Mol Endocrinol 21:457-71 |
