The orphan nuclear receptor steroidogenic factor1 (SF-1), originally isolated as a regulator of the cytochrome P450 steroid hydroxylases, plays essential roles in endocrine development and function. SF-1 knockout mice lack adrenal glands and gonads, have impaired pituitary gonadotrope function, and lack the ventromedial hypothalamic nucleus (VMH), a hypothalamic region linked to appetite control and reproductive behavior. Ongoing studies seek to expand our understanding of these pleiotropic roles of SF-1 and to separate primary versus secondary components of the knockout phenotype. The developing technology for tissue- specific knockouts will be used to disrupt the gene encoding SF-1 specifically within individual sites, including: the VMH, pituitary gonadotropes, Sertoli cells, or granulosa cells. Alternatively, adrenal transplants will restore adrenocortical function in SF-1 knockout mice, permitting analyses of VMH- ablated mice in the setting of normal levels of adrenocortical steroids. A related series of experiments will use green fluorescent protein (GFP) or beta-galactosidase (LacZ) transgenes directed by SF-1 regulatory sequences to follow SF-1 expressing neurons ex vivo in hypothalamic slice preparations, comparing VMH development in wild-type and SF-1 knockout mice. Finally, we will use zone-specific ablation to investigate the mechanisms that compartmentalize the adrenal gland into the outer zona glomerulosa, which makes mineralocorticoids, and the inner zonae fasciculata/reticularis, which make glucocorticoids. These studies will provide novel insights into the ways in which SF-1 exerts its multiple actions in endocrine development and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054480-04
Application #
6517511
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$341,737
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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