SF1--KEY MEDIATOR OF ENDOCRINE DEVELOPMENT AND FUNCTION

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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.