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 and segregation 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 newly-discovered mechanisms and 2) to shed light on how they are regulated. An important component of this kinetochore-independent segregation system is a complex of proteins that form a ring structure around the center of each chromosome pair (the ?midbivalent ring?). Our work will therefore delve into the assembly, disassembly, organization, and functions of this ring complex, to reveal mechanisms essential for chromosome segregation on acentrosomal spindles. Moreover, we have also recently discovered that a regulatory mechanism exists in these cells; in the presence of meiotic errors, oocytes delay key events in anaphase progression, potentially to increase the fidelity of chromosome segregation. Therefore, we will use a combination of approaches to investigate error regulation in these cells and to expand and refine our models for chromosome congression and segregation. These approaches will enable us to gain a mechanistic understanding of oocyte meiosis, an important yet poorly understood form of specialized cell division.
It is estimated that 10-25% of human embryos are chromosomally abnormal, resulting in a high incidence of miscarriages and birth defects. Most of these abnormalities are the result of chromosome segregation defects in the female reproductive cells (oocytes), yet surprisingly little is known about the mechanisms that underlie the vulnerability of oocytes to cell division errors. This project seeks to reveal mechanisms that mediate accurate chromosome partitioning in oocytes, providing insight into this important question.
|Davis-Roca, Amanda C; Divekar, Nikita S; Ng, Rachel K et al. (2018) Dynamic SUMO remodeling drives a series of critical events during the meiotic divisions in Caenorhabditis elegans. PLoS Genet 14:e1007626|