Regulation of chromosome segregation during oocyte meiosis

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Project Summary Organisms that reproduce sexually utilize a specialized cell division program called meiosis to reduce their chromosome number by half to generate haploid gametes. Proper execution of this process is crucial for a successful pregnancy, since errors in meiotic chromosome segregation result in aneuploidy (incorrect chromosome number in the embryos), the leading known cause of miscarriages and birth defects in humans. Meiosis in females is especially error prone and this vulnerability has a profound impact on human health: it is estimated that 10-25% of human embryos are chromosomally abnormal, and the vast majority of these defects arise from problems with the female meiotic cells (called oocytes). However, despite the importance of female meiosis for successful reproduction and human health, surprisingly little is known about the mechanisms that act to ensure accurate chromosome partitioning in oocytes. Oocytes have some special features that necessitate the use of novel cell division mechanisms. Perhaps most significantly, oocytes lack centrosomes, which define and organize the spindle poles in other cell types; therefore, spindles in these cells are morphologically distinct. Using C. elegans as a model, we previously found that acentrosomal oocyte spindles have a surprising organization; chromosomes are ensheathed by microtubule bundles that run along their sides, making lateral contacts, instead of forming end-on kinetochore attachments. Moreover, we also defined new mechanisms that facilitate chromosome congression on these spindles, driven by movement of chromosomes along these lateral bundles. Therefore, our work has revealed a new strategy utilized by C. elegans oocytes for controlling chromosome dynamics during cell division. Building on these discoveries, the goals of the proposed work are to: 1) deepen our understanding of these unique mechanisms, and 2) identify factors that regulate them. An important component of this system is a complex of proteins that form a ring structure around the center of each chromosome pair (the “ring complex”). Our work will therefore delve into the functions of this ring complex, to reveal mechanisms essential for proper acentrosomal spindle organization and chromosome dynamics. These approaches will enable us to gain a mechanistic understanding of oocyte meiosis, an important yet poorly understood form of specialized cell division.