ROLE OF SF1 AND DAX1 IN OVARIAN FUNCTION

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FSH, acting primarily through the protein kinase A pathway, regulates follicular development and function. Recent studies reveal convergence of the FSH/cAMP pathway with a group of transcription factors (SF-1, DAX-1) that control target genes in the ovary. SF-1 and DAX-1 are orphan nuclear receptors that play a key role in the development and function of the adrenal, gonads, and pituitary gonadotropes. A gene knock-out of SF-1 prevents the development of these organs, and SF-1 response elements have been identified in promoters of many different ovarian genes. Mutation of the X-linked DAX-1 gene causes the syndrome of adrenal hypoplasia congenital. It is characterized by the absence of the adult zone of the adrenal cortex with hypogonadotropic hypogonadism with apparently normal testicular Leydig cell function. Duplication of DAX-1 causes sex reversal in genetic males, and DAX-1 has been postulated to foster ovarian development. We have shown that DAX-1 modulates SF-1 action and play a critical role in ovarian development and function. We have shown that DAX- 1 modulates SF-1 action and hypothesize that the balance of DAX-1 and SF-1 expression in the ovary regulates its development, and subsequently, the function of various target genes like inhibin-alpha and steroidogenic enzyme genes. We propose an integrated group of in vitro and in vivo studies to further define the functions of SF-1 and DAX-1 in the ovary. There are three specific aims: 1) To examine mechanisms by which the cAMP and SF-1 pathways interact to regulate ovarian genes. We hypothesize that transcriptional co-factors, such as CBP, provide a basis for convergence of the FSH signaling pathway with the nuclear receptor, SF-1; 2) To determine the basis of divergent effects of DAX-1 on SF-1-mediated transcription of different ovarian target genes. We hypothesize that DAX-1 promoters will be studied as representative examples of SF-1 responsive genes that are regulated differentially by DAX-1; 3) To determine the effect of targeted deletion and over-expression of DAX-1 on ovarian gene expression. These studies will test in vivo whether DAX-1 plays a role in ovarian development and in the regulation of ovarian gene expression.