TRANSCRIPTION FACTOR INTERACTIONS IN REPRODUCTIVE HORMONE GENE EXPRESSION

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The actions of inhibin and activin as modulators of pituitary FSH synthesis and secretion and as local regulatory factors within the gonads makes them of key significance for maintaining reproductive fitness and suggests their involvement in reproductive dysfunction (114). Neutralization of inhibin increases follicular maturation and ovulation in animals (115, 116). Ablation of the a inhibin gene in mice results in formation of gonadal stromal cell tumors, implicating inhibin as a tumor-suppressor gene (117). Conversely, over-expression of inhibin in mice results in suppressed fertility and disrupted folliculogenesis (118). In the human, inhibin is an early marker for some types of ovarian cancer (6), is inappropriately regulated in polycystic ovarian syndrome (7) and may be mutated in some cases of premature ovarian failure (8, 9). Transcription factors regulating inhibin expression are also involved in human disease (119, 120), with perhaps the best example being SF-1 mutations in gonadal and adrenal insufficiency and XY sex-reversal (121, 122). This proposal is aimed at understanding how the inhibin gene is expressed and regulated by the pituitary gonadotropins in the ovary and in follicular granulosa cells, focusing on the structural features and interactions of the transcription factors and coactivators important for this regulation. Figure 2 outlines our current understanding of inhibin gene expression during the reproductive cycle, and points to key aspects of this regulation that we plan to further investigate. While the proposed experiments will focus on the inhibin a subunit gene, we expect these findings to be broadly applicable to understanding gonadotropinand cAMP-dependent signaling pathways regulating gene expression in the mammalian ovary. This basic knowledge is expected to provide a foundation for better understanding aberrations of reproductive hormone synthesis and action that in turn lead to dysfunctions or diseases of importance to human health with implications for the treatment of infertility or regulation of fertility (see also Project IV).