Failure to achieve accurate chromosome segregation during meiosis can lead to miscarriages, infertility, tumorigenesis and birth defects such as Down syndrome. The clear and significant impact to reproductive health of successfully producing haploid gametes (i.e. eggs and sperm) from diploid germ cells makes it of paramount importance to understand the mechanisms underlying accurate chromosome segregation during meiosis. A ubiquitously present, and yet poorly understood, feature of meiosis is the zipper-like structure known as the synaptonemal complex (SC). It is known that the SC stabilizes homologous pairing interactions, is essential for crossover formation between homologs, and therefore, required for proper chromosome segregation at meiosis I. However, the mechanisms regulating SC assembly and disassembly, as well as the orchestrated chromosome remodeling process that initiates as the SC disassembles, are not well understood in any organism. Our goal is to address these critical issues by taking advantage of the ease of genetic, cytological, molecular and biochemical analysis that is afforded by the use of the nematode C. elegans, an ideal model system for germline studies. Our progress during the previous funding period, coupled with new data and technology, has revealed several molecular entry points that place us in an ideal position to understand the regulation of chromosome synapsis and chromosome remodeling. Here we propose a set of three integrated aims to address these critical biological processes.
Aim 1 will address how NatB-mediated N- terminal acetylation of meiotic proteins regulates SC assembly; this will focus on a new mechanism for regulating chromosome synapsis driven by a highly prevalent co-translational modification in eukaryotes, but for which very few biological functions have been ascribed so far.
Aim 2 will determine the mechanisms of function for GRAS-1, a new and conserved protein of previously unknown meiotic function, which our studies implicate in regulating SC assembly and we hypothesize may act as a molecular scaffold for structural components of the SC.
Aim 3 will define how the MAP kinase pathway regulates SC assembly, disassembly, and chromosome remodeling;
this aim will incorporate our discovery of ECT-2, the homolog of human Rho guanine nucleotide exchange factor, to examine how the MAP kinase pathway modulates synapsis and chromosome remodeling in late meiotic prophase. These studies will shed new light on our understanding of the mechanisms regulating SC assembly, disassembly and chromosome remodeling. Our studies are expected to impact multiple fields of tremendous relevance to human health including chromosome dynamics, the study of co-translational modifications, regulation of macromolecular structures and signal transduction. Taken together, this application will provide significant new insights into the molecular mechanisms regulating accurate chromosome segregation during meiosis.
Meiotic cell divisions are essential for the formation of both eggs and sperm and therefore of critical importance for human reproductive health. Errors during meiosis result in miscarriages, infertility, tumorigenesis and birth defects such as Down syndrome. This application will investigate the molecular mechanisms promoting accurate chromosome segregation during meiosis thereby establishing the foundation for the development of effective preventive strategies.
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