Control of mammalian meiosis I through protein kinase signaling

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DESCRIPTION (provided by applicant): Chromosome segregation during meiosis I (MI) is unique because homologous chromosome pairs segregate. In humans, mistakes in MI occur are strikingly high in female gametes (oocytes), resulting in infertility, miscarriage, or birth defects. The molecular mechanisms that control MI are poorly understood. The goal of this proposal is focused on dissecting the mechanisms that the Aurora B and Aurora C protein kinases use to control MI to explain this phenomenon. The Aurora protein kinase family is an essential regulator of chromosome segregation in mitosis, and Aurora activity is required for completing a normal MI segregation. Aurora C kinase (AURKC) expression is highly up- regulated in gametes. Yet, because AURKC shares high sequence homology with Aurora B kinase (AURKB) standard approaches to understand their MI-specific functions are not sufficient. We have begun to unravel the mystery of why oocytes contain 2 kinases that are similar to one another, and have identified AURKC functions during MI in mouse oocytes that are distinct from AURKB. These functions include ensuring normal chromosome alignment at the metaphase I plate and chromosome segregation to maintain proper chromosome numbers through controlling incorrect microtubule attachments to chromosomes. In this proposal, we aim to fully determine the MI functions of both AURKB and AURKC. We have generated mice that lack Aurkb and Aurkc in their oocytes to conduct more thorough analyses of AURK function using a chemical genetics strategy. This strategy will be used in Aim 1 to investigate the molecular mechanisms of AURKB and AURKC in microtubule dynamics and cytokinesis during MI. This aim will test the hypothesis that some functions are distinct, whereas other functions are overlapping. We have demonstrated that AURKC has a unique localization along chromosome arms at the interchromatid axes during metaphase I that is not found in mitotic metaphase. In Aim 2 we develop strategies to perturb the localized activity of AURKC at the axes to test the hypothesis this localized AURKC activity controls meiotic chromosome condensation during MI. Information gained from our studies will help us fully understand how these kinases operate during MI while highlighting distinct differences between how mitosis and MI are controlled. Importantly, these data will shed light on how MI chromosome segregation is controlled in oocytes and why it commonly goes awry in women leading to chromosome segregation errors.