Fertility and TAF4b: Transcriptional Regulation of Murine Ovarian Reserve Establishment

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Female infertility is a common health concern in the United States. Primary ovarian insufficiency (POI) is characterized by premature menopause and it leads to infertility in 1% of the female population, but the cause of infertility cannot be determined in most cases. Although POI is often diagnosed in adult life, this condition likely stems from poor establishment of the ovarian reserve during embryonic development. The ovarian reserve is composed of primordial follicles, each of which contain a single oocyte surrounded by a layer of pre-granulosa cells. Meiosis and early oogenesis are two key contributors to the success or failure of primordial follicle development, but the transcriptional controls regulating these early processes in the female germline are poorly understood. The focus of my research is TBP-Associated factor 4b (TAF4b), which is a gonadally-enriched subunit of the general transcription machinery and it is essential for female fertility. Female mice lacking TAF4b display multiple aspects of POI and exhibit critical defects in meiosis and oogenesis. The effects of Taf4b- deficiency in the mouse can be traced back to meiotic initiation, but the function of TAF4b during this process has remained elusive. The goal of this proposal is to develop a comprehensive understanding of how TAF4b contributes to the gene regulatory network that drives expression of meiotic genes and successful establishment of the ovarian reserve. Aim 1 will use a powerful in vitro system of early oocyte development to elucidate the precise role of TAF4b in meiotic initiation and adoption of the oogenic fate. Aim 2 will use an in vivo approach to evaluate how and when TAF4b interacts with other factors that regulate meiosis and oogenesis. Ultimately, this proposal will clarify how components of the general transcription machinery regulate gene expression that is essential for proper progression of meiosis and oogenesis, and thus it will significantly contribute to the field’s understanding of female germ cell development. While completing these aims, I will develop a repertoire of skills and the key foundational knowledge required for a successful career in reproductive biology research. My training experience will be enriched by attending the Frontiers in Reproduction course in Woods Hole, presenting at national and international conferences, and thoughtful mentoring by my sponsor. Moreover, completion of this proposal will take place in the outstandingly supportive Molecular Biology, Cell Biology, and Biochemistry Graduate Program at Brown University. Completion of this fellowship will move the developmental biology field forward and provide me with the exceptional preparation required for the achievement of my career goal to lead an independent academic research laboratory focused on reproductive biology.