Molecular Mechanisms of Meiotic Maturation in Drosophila

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DESCRIPTION (provided by applicant): Meiosis is a fundamental process that is coupled to gamete development. Oocytes arrest in prophase of the first meiotic division to allow for growth. Release from prophase I occurs during meiotic maturation, but the molecular mechanisms regulating this process are incompletely understood. Meiotic maturation defects can result in infertility or in inaccurate segregation of chromosomes, leading to miscarriages and/or birth defects. The fruitfly Drosophila melanogaster offers sophisticated genetic and molecular tools, and a well described ovarian cell biology, making it a powerful system to investigate the control of meiotic maturation. Drosophila oocytes enter meiosis shortly after germline cyst formation and arrest in prophase I during most of their development. After meiotic maturation, oocytes arrest again in metaphase I until ovulation. In the prior funding period, we demonstrated that 1-Endosulfine (Endos) is required for meiotic maturation. Our data suggest that Endos promotes the stability of the cell cycle regulators CyclinA, Polo and Twine/Cdc25 (all known to be targets of the Anaphase Promoting Complex, or APC), and that it also has a separate role via inhibition of the E3 ubiquitin ligase Elgi to promote meiotic maturation. Expression of ENSA, the human 1- endosulfine, rescues the endos meiotic defect, and 1-endosulfine is expressed in mouse oocytes, suggesting conservation of the meiotic function of 1-endosulfine. Our overarching hypothesis is that Endos is a central regulator of meiotic maturation via two mechanisms: it inhibits the activity of the APC to allow the accumulation of key cell cycle regulators, and it antagonizes the ubiquitination of Elgi targets. We will test this hypothesis through the following specific aims: 1) to determine if Endos is a negative regulator of the APC; 2) to determine how the E3 ubiquitin ligase Elgi regulates meiotic maturation downstream of Endos; and 3) to elucidate the molecular mechanism of action of Endos. Elucidation of the molecular mechanisms of meiotic maturation could potentially lead to therapies to address this cause of infertility, as well as to new contraceptives. Furthermore, this knowledge could also lead to technological strategies for in vitro maturation of human oocytes to complement current in vitro fertilization methodology. PUBLIC HEALTH RELEVANCE: Failure of the oocyte to undergo meiotic maturation leads to infertility. Our prior work has identified Endos as a major regulator of meiotic maturation, and we propose to use powerful research tools in fruitflies to understand the function of this protein. Our studies could potentially lead to additional therapies to address infertility, as well as to technological strategies to complement current in vitro fertilization methodology.