The actions of inhibin and activin as modulators of pituitary FSH synthesis and secretion and as localregulatory factors within the gonads makes them of key significance for maintaining reproductive fitnessand suggests their involvement in reproductive dysfunction (114). Neutralization of inhibin increasesfollicular maturation and ovulation in animals (115, 116). Ablation of the a inhibin gene in mice results information 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 inappropriatelyregulated in polycystic ovarian syndrome (7) and may be mutated in some cases of premature ovarianfailure (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 XYsex-reversal (121, 122).This proposal is aimed at understanding how the inhibin gene is expressed and regulated by thepituitary gonadotropins in the ovary and in follicular granulosa cells, focusing on the structural features andinteractions of the transcription factors and coactivators important for this regulation. Figure 2 outlines ourcurrent understanding of inhibin gene expression during the reproductive cycle, and points to key aspectsof this regulation that we plan to further investigate. While the proposed experiments will focus on theinhibin a subunit gene, we expect these findings to be broadly applicable to understanding gonadotropinandcAMP-dependent signaling pathways regulating gene expression in the mammalian ovary. This basicknowledge is expected to provide a foundation for better understanding aberrations of reproductivehormone synthesis and action that in turn lead to dysfunctions or diseases of importance to human healthwith implications for the treatment of infertility or regulation of fertility (see also Project IV).
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