The orphan nuclear receptor steroidogenic factor 1 (SF-1) plays essential roles in endocrine development and function. SF-1 knockout (KO) mice exhibit adrenal and gonadal agenesis, impaired pituitary gonadotrope function, and marked structural abnormalities of the ventromedial hypothalamic nucleus (VMH). The proposed studies seek to expand our understanding of these pleiotropic roles of SF-1, focusing specifically on its roles in gonadal development. First, we will use the Cre-loxP technology to inactivate SF-1 in specific cell lineages of the testes and ovaries. By using different promoters to direct Cre expression, we envision that we will achieve both cell-type specific inactivation as well as inactivation at different stages of development. We also will use a transgenic enhanced green fluorescent protein (eGFP) reporter gene directed by SF-1 regulatory sequences to purify SF-l-expressing cells from the gonads of wild-type and SF-1 KO mice, allowing us to compare gene expression profiles of the same cell populations in the presence or absence of SF-I. We will use transient transfection experiments with the 5-flanking regions of these candidate genes to determine if they are direct or indirect targets of SF-1. To develop a mechanism to inactivate the expression of genes of interest from early stages of gonadogenesis, we will use BAC transgenesis to target expression of Cre recombinase to the sites where SF-1 is expressed. Finally, we will attempt to define the sequences that regulate SF-1 expression in the gonads, focusing on a conserved sequence in the 6th intron that is associated with a DNase hypersensitive site. These studies will provide novel insights into how SF-1 exerts its multiple actions in gonadal development and function.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046743-02
Application #
6871339
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Taymans, Susan
Project Start
2004-04-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$315,900
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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