Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis

Project Summary/Abstract Meiosis is the cell division process that is essential for sexual reproduction because it creates haploid gametes from diploid precursor cells. In humans, mistakes in meiosis I (MI), the unique chromosome segregation where homologous chromosomes separate, occur at a strikingly high frequency in female gametes (oocytes). These mistakes can cause miscarriage or birth defects, yet the molecular mechanisms that control MI are poorly understood. Work in our lab has been instrumental in dissecting the cellular requirements of the Aurora protein kinases used to control MI in mouse oocytes to understand the basic mechanisms that could go awry and cause this phenomenon. The Aurora protein kinase family is comprised of three members: AURKA, AURKB and AURKC. The Aurora kinases are essential regulators of chromosome segregation in mitosis, and their activities are required for completing MI chromosome segregation. AURKC expression is limited to gametes and is aberrantly expressed in some cancers. Our expertise in creating and evaluating oocyte specific AURK knockout mice has allowed us to determine why oocytes require three Aurora kinases. In the past funding period, we identified AURKB and AURKC functions that are distinct from one another, uncovered that the three AURKs regulate one another and elucidated the steps in meiotic spindle assembly dependent upon AURKA. The MIRA funding also supported a new line of inquiry where we described unique features of meiotic midbodies during MI completion. The objective of our work is to understand why the Aurora kinases are important for maintaining genome integrity in oocytes. To reach this objective, in the next five years we propose to expand our scope to explore AURKA requirements for controlling protein homeostasis processes such as localized translation and regulation of the oocyte specific subcortical maternal complex. We will also evaluate requirements for AURKA and AURKC in completing MI by evaluating abscission timing and formation of a meiotic midbody structure we call a cap. Information gained from our studies will help us fully understand how these kinases operate during MI. Importantly, our results will shed light on how mammals make high quality gametes and why it commonly goes awry in humans leading to aneuploidy.