Defining the Mechanism of Meiotic Initiation Through Autophagy Pathway

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PROJECT SUMMARY The ovary is not only a reproductive organ but also an endocrine organ that produces hormones, including estrogen, testosterone, and progesterone—which are vital to women’s reproductive organ, breast development, bone health, and pregnancy. Thus, the ovary is critical to women’s fertility and health. Inside the ovary, ovarian follicles (oocytes enclosed by granulosa cells) are the basic functional unit. However, early depletion of oocytes is a major cause of primary ovarian insufficiency (POI), which affects 5-10% women worldwide. Oogenesis (formation of oocytes) in women starts during fetal development, when primordial germ cells (PGCs) exit mitosis and enter meiotic prophase I (a process termed “meiotic initiation”) to carry out homologous recombination. This is in contrast with spermatogenesis, which does not occur upon puberty in men. At birth, the ovary is filled with meiotically arrested oocytes in follicle structures. Meiotic initiation is essential for oocyte formation, in that genetic disruption of this process results in a near-complete loss of oocytes in adult ovaries. Additionally, during meiotic prophase I, defective homologous recombination results in meiotic chromosome segregation errors and oocytes carrying an incorrect number of chromosomes (aneuploidy), a leading cause of poor pregnancy and fetal outcomes. Thus, proper meiotic initiation ensures both the quantity and the quality of oocytes. However, the molecular mechanism underlying meiotic initiation is poorly understood. We have reported that stimulated by retinoic acid gene 8 (STRA8), a gatekeeper of meiotic initiation in vertebrates, acts as a suppressor of autophagy. As such, loss of STRA8 results in an uncontrolled autophagy activation in germ cells during both spermatogenesis and oogenesis. Based on this information, the parent grant studies autophagic regulation of meiotic initiation in the context of spermatogenesis. Our hypothesis is that STRA8-mediated suppression of autophagy allows accumulation of proteins required for meiotic gene activation and initiation; in the absence of STRA8, these proteins are degraded by autophagy, precluding meiosis. This Administrative Supplement extends our study from spermatogenesis to oogenesis. We will: 1. Investigate the role of autophagy suppression in meiotic initiation in fetal ovaries; 2. Define the molecular links between autophagy and meiotic initiation in fetal ovaries. Aberrant autophagy due to genetic or environmental causes is often linked to human diseases. Meanwhile, autophagy pathway represents an intriguing druggable target. Thus, upon completion, knowledge gained from Administrate Supplement may provide insights into the etiology of POI from the perspective of autophagy dysregulation and offer novel pretherapeutic opportunities to improve women’s health.