Fertility and TAF4b: Transcriptional Regulation of Murine Ovarian Reserve Establishment

在美国，女性不孕症是一个常见的健康问题。原发性卵巢功能不全（POI）的特点是过早绝经，在1%的女性人口中导致不孕，但在大多数情况下无法确定不孕的原因。虽然POI通常在成人生活中被诊断出来，但这种情况可能源于胚胎发育期间卵巢储备的不良建立。卵巢储备由原始卵泡组成，每个原始卵泡含有一个卵母细胞，卵母细胞被一层前颗粒细胞包围。减数分裂和早期卵发生是决定原始卵泡发育成败的两个关键因素，但调控这些早期过程的转录调控在女性生殖系中尚不清楚。我的研究重点是TBP-Associated factor 4b (TAF4b)， TAF4b是一般转录机制中富含性腺的亚基，对女性生育至关重要。缺乏TAF4b的雌性小鼠表现出POI的多个方面，并在减数分裂和卵子发生方面表现出严重缺陷。Taf4b-缺乏对小鼠的影响可以追溯到减数分裂起始，但Taf4b在这一过程中的功能仍不明确。本提案的目标是全面了解TAF4b如何参与驱动减数分裂基因表达和成功建立卵巢储备的基因调控网络。目的1将使用一个强大的早期卵母细胞体外发育系统来阐明TAF4b在减数分裂起始和卵源命运采用中的确切作用。Aim 2将使用体内方法来评估TAF4b如何以及何时与调节减数分裂和卵子发生的其他因子相互作用。最终，该建议将阐明一般转录机制的组成部分如何调节基因表达，这对于减数分裂和卵发生的正常进展至关重要，因此它将显著有助于该领域对女性生殖细胞发育的理解。在完成这些目标的同时，我将培养一个成功的生殖生物学研究职业所需的技能和关键基础知识。我的培训经历将通过参加伍兹霍尔的生殖前沿课程，在国内和国际会议上发表演讲，以及我的赞助商的周到指导而丰富。此外，该提案将在布朗大学的分子生物学、细胞生物学和生物化学研究生课程中完成。该奖学金的完成将推动发育生物学领域的发展，并为实现我的职业目标——领导一个专注于生殖生物学的独立学术研究实验室——提供所需的特殊准备。

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.