Infertility is a common issue across the United States, with 1% of all women being affected by primary ovarian insufficiency (POI) and 70% of these POI cases being idiopathic. Fertility problems such as POI can be caused by early defects in the development of the ovarian reserve. Meiosis is one such contributor to the success or failure of establishing a healthy primordial follicle pool in the ovarian reserve. Despite the critical importance of meiosis in fertility, the sex-specific characteristics of early female meiosis and the transcriptional controls regulating these early events in the female germline are poorly understood. The focus of my research, and a regulator of meiosis, is TBP-Associated Factor 4B (TAF4B), a gonadally-enriched member of the general transcription machinery. Mice deficient in functional TAF4B have been shown to display multiple aspects of POI and critical defects in early meiotic events and gene expression. The effects of Taf4b-deficiency in the mouse have been traced as far back in development as embryonic day 13.5 (E13.5), when meiosis initiates. I will create a comprehensive model of the transcriptional regulation required for the expression of meiotic genes and successful execution of meiotic initiation via TAF4B.
Aim 1 will elucidate the protein characteristics and interactions of TAF4B before, during, and after meiotic initiation.
Aim 2 will explore the TAF4B-dependent gene program node of meiotic initiation in female germ cells at E13.5, determining which genes are indirectly or directly regulated by TAF4B and the overall impact on meiotic initiation. This proposal will be of significant interest to the reproductive biology field because it will be the first study to examine how selective components of the general transcription machinery work together with germ-cell specific machinery to promote meiotic initiation. One of this fellowship's training goals is to develop the repertoire of skills and body of knowledge for a successful career in reproductive biology research. The second goal is to gain experience in effectively communicating research in a variety of settings. To achieve these goals, completion of the proposed research, attending the Frontiers in Reproduction course in Woods Hole, presenting at national and international conferences, and the sponsor's mentoring will ensure the success of this training plan. Furthermore, this proposal will take place in the excellent environment of the interdisciplinary and supportive Molecular Biology, Cell Biology, and Biochemistry program at Brown University. Completion of this research and training plan will move the reproductive biology field forward and give the ideal preparation towards the career goal of leading an independent academic research laboratory focused on reproductive biology.
Infertility in the form of the syndrome primary ovarian insufficiency (POI) affects at least 1% of the human female population, however in most cases the mechanisms causing POI are unknown. Understanding the molecular mechanisms that contribute to the development of a healthy ovarian reserve of oocytes is critical to improving current treatments for both POI patients and individuals utilizing the field of Assisted Reproductive Therapy (ART). This project examines the characteristics and mechanistic function of an ovary-enriched factor in regulating the healthy development of oocytes in the complex process of meiosis.