Understanding the role of meiotic misregulation in germ cell tumor formation

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Meiosis is precisely regulated to ensure the transmission of half the genome into gametes. During meiosis, germ cells undergo one round of DNA replication followed by two rounds of chromosome segregation. In mammalian females, meiosis is an error-prone process, resulting in a high fraction of eggs with missing or extra chromosomes or that are not competent for fertilization. These errors can cause severe consequences including miscarriage, trisomy conditions, infertility, germ cell tumor formation, and ovarian germ cell cancer. Therefore, determining the molecular mechanisms underlying meiotic regulation is critically important for understanding the etiology of these disorders. The objective of this proposal is to investigate how meiosis II is controlled to ensure an egg competent for fertilization and to understand how errors in meiosis II regulation result in uncontrolled cell proliferation and the formation of germ cell tumors. These studies employ the use of mouse as a mammalian model system to use the tools available to address mechanistic questions. Female mice are used to study the oogenesis-specific question of how eggs arrest in meiosis II to await fertilization from sperm before completing the second meiotic division. The rationale for the proposed research is that the questions were chosen to focus on the understudied and poorly understood process of meiosis II regulation, which is important to ensure competent eggs and to prevent germ cell tumor formation. These findings are likely to be highly conserved in mammals, such that the results from mouse oogenesis will uncover general mechanisms of meiotic regulation during human oogenesis. The experiments are guided by the following specific aims proposed: 1) Determine how CDK-cyclin B1 activity is regulated for meiosis II and meiosis II arrest; and, 2) Investigate how mos-/- mutant eggs undergo inappropriate cell divisions and identify other meiotic regulators whose loss could cause ovarian germ cell tumors. For Aim 1, novel hypotheses are tested that address how protein translation and degradation are regulated during meiosis II and how RNA-binding proteins release mRNAs with appropriate timings. In Aim 2, the results will reveal how meiosis is mis-regulated when the MOS/MAPK signaling pathway is disrupted. Finally, new meiosis II regulators will be discovered. The innovative approaches of combining the latest imaging and genomics technologies with the power of in vitro oocyte maturation will allow the discovery of new mechanisms of meiotic regulation. The proposed research is significant because the results will reveal general principles of meiotic regulation and will identify new targets for germ cell cancer prevention.