A set of well-orchestrated signals that regulate gonadotropin gene expression drive reproductive function. Gonadotropin production is primarily directed by hypothalamic gonadotropin releasing hormone (GnRH), and modulated by feed-back signals from the pituitary and gonad. This proposal focuses on female reproduction, centering on the mechanisms that direct expression of the unique beta-subunit of luteinizing hormone (LHbeta). Along with the common alpha-subunit, the two subunits constitute the """"""""mature"""""""" hormone. Among the signals that operate through discrete elements within the LHbeta gene promoter and determine its expression, two transcription factors are distinguished for their prominent role: 1. Egr- 1, a prototype of a family of early growth response (Egr) gene products and essential for LHbeta expression; and 2. The nuclear receptor steroidogenic factor-1 (SF-1), which is potent activator of LHbeta promoter, albeit not required for basal LHbeta production. Through meticulous examination of the transcriptional function of these proteins, our lab has recently unveiled a powerful synergy between these proteins in regulation of LHbeta transcription. The mechanism of Egr-1 and SF-1 synergy, as well as the role of this synergy in reproductive biology, remain elusive. Our proposed experiments build on these findings, and are designed to test the hypothesis that synergistic interaction of SF-1 with Egr-1 and its family members determines gonadotrope expression of LHbeta gene in vitro and in vivo. To test this hypothesis, we will address four questions central to female reproduction: What is the mechanism or SF-1-Egr-1 synergy? Which other proteins play a role in this synergy? Are Egr-1 and SF-1 targets for regulation by GnRH? Does insulin-mediated enhancement of LHbeta production occur through the cooperative interaction of, Egr-1 and SF-1? Both in vitro and in vivo approaches will be used to answer these questions. Our study is of paramount significance to the analysis of LHbeta regulation. Enhanced expression of LHbeta disrupts normal reproductive homeostasis in the female, and is implicated in the pathophysiology of diseases such as polycystic ovary syndrome (PCOS), characterized by infertility, hyperandrogenism, and polycystic ovaries. Our examination of SF-1 and Egr-1 function does not imply that these proteins play a role in the pathophysiology of PCOS. However, our results are likely to shed light on mechanisms that lead to enhanced LHbeta expression, and they may therefore provide a framework for a novel therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037571-03
Application #
6388088
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
De Paolo, Louis V
Project Start
1999-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$203,073
Indirect Cost
Name
Washington University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Vachharajani, Akshaya; Bethin, Kathleen; Mouillet, Jean-Francois et al. (2006) The rare occurrence of absent adrenals in a term infant: a case report and review of the literature. Am J Perinatol 23:111-4
Mouillet, Jean-Francois; Sonnenberg-Hirche, Christina; Yan, Xiaomei et al. (2004) p300 regulates the synergy of steroidogenic factor-1 and early growth response-1 in activating luteinizing hormone-beta subunit gene. J Biol Chem 279:7832-9
Dorn, Christoph; Mouillet, Jean-Francois; Yan, Xiaomei et al. (2004) Insulin enhances the transcription of luteinizing hormone-beta gene. Am J Obstet Gynecol 191:132-7
Yan, Xiaomei; Mouillet, Jean-Francois; Ou, Qinglin et al. (2003) A novel domain within the DEAD-box protein DP103 is essential for transcriptional repression and helicase activity. Mol Cell Biol 23:414-23
Ou, Q; Mouillet, J F; Yan, X et al. (2001) The DEAD box protein DP103 is a regulator of steroidogenic factor-1. Mol Endocrinol 15:69-79
Sadovsky, Y; Dorn, C (2000) Function of steroidogenic factor 1 during development and differentiation of the reproductive system. Rev Reprod 5:136-42