Dynamic Regulation of the Ovarian Reserve

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Project Summary Approximately 12% of couples are infertile and 1% of the female population worldwide experiences primary ovarian insufficiency (POI) which results from a reduction of the ovarian follicle reserve that often leads to premature menopause and infertility. Important pathological outcomes associated with early menopause include osteoporosis, cardiovascular and Alzheimer's disease. Although several genes have been linked to women with POI, about 90% of the cases are idiopathic. By uncovering the developmental and molecular mechanisms underlying the establishment of the initial pool of primordial follicles and the maintenance of the adult ovarian reserve in the mouse, we will be poised to better understand, diagnose and treat POI in the future. We have discovered and characterized the roles of a protein called TAF4b that is essential for establishing the healthy ovarian follicle reserve in the mouse ovary. TAF4b is a gonadal-enriched subunit of the general transcription factor TFIID, a large multiprotein complex composed of the TATA-box binding protein (TBP) and 14 TBP- associated factors (TAFs). Our approach to studying the regulation of ovarian follicle development by TAF4b has elucidated the ovarian functions of TAF4b in the context of a TAF4b-deficient mouse model. Collectively, these studies have revealed that TAF4b-deficient female mice suffer from hallmarks of POI including persistent estrous, elevated serum follicle stimulating hormone (FSH) and accelerated ovarian reserve depletion. In addition to our own work, a number of additional studies have linked the potential function of human TAF4b in the regulation of fertility in women. Strikingly, some of the genetic networks regulated by TAF4b in the mouse ovary appear to be conserved during human fetal ovary development. Together, these data implicate the potential deregulation of TAF4b-regulated processes in the context of human POI and female infertility. Based upon our previous studies, we hypothesize that diverse TAF4b-regulated transcriptional events in the developing mammalian ovary serve to properly maintain normal ovarian aging and fertility. By uncovering the oocyte- and granulosa cell-specific functions and mechanisms of TAF4b in these studies, we aim to identify novel genes and expression mechanisms in place to ensure the successful production of high quality oocytes in women and perhaps one day better diagnose and/or manage patients with POI and other related deficits of human ovarian health.