Molecular control of oocyte arrest, meiosis, and the transition to development

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7. Project Summary / Abstract Animal reproduction requires the production of sperm and eggs which undergo fertilization to construct a new organism through embryogenesis. To accomplish this feat, the cell division machinery must undergo a dramatic series of modifications to adapt to these developmental transitions. Human oocytes arise embryonically and arrest in meiotic prophase, where they will remain for as long as decades until a hormonal stimulus triggers their growth and cell cycle re-entry. After enduring this extended arrest, oocytes must accurately segregate chromosomes in meiosis, be fertilized, and then divide with high fidelity. It is well- appreciated that human oocytes lose their competency for meiosis, fertilization, and development as the length of this arrest and the maternal age increases, resulting in markedly increased incidence of aneuploidies, miscarriage and development disorders. The ability of an oocyte to persist through prophase arrest is therefore of paramount importance for the human life cycle, but is a challenging state to study, and we know relatively little about how it is molecularly regulated. The goal of this proposal is to define the molecular program that maintains oocyte competency for future division during extended arrest, and how this state is influenced by the ovarian environment. A challenge for addressing this question has been the limited availability of mammalian oocytes, which are among the rarest cells in the body. To address this challenge, I have developed strategies for extended in vitro culture of biochemical quantities of oocytes from the sea star Patiria miniata, a powerful model organism whose oocytes share common features and conserved molecular mechanisms with humans. Leveraging this advantage, I will perform a series of cell biological and high-throughput analyses to interrogate the transcriptional, translational, and post-translational mechanisms that oocytes enact to enforce and persist through their extended arrest. This approach will open new doors for understanding important aspects of human fertility, and will enable my transition to independence as an investigator committed to the study of development and fertility.