Failure to achieve accurate chromosome segregation during meiosis is a leading cause of miscarriages, infertility, and birth defects such as Down syndrome. Therefore, understanding the mechanisms underlying accurate chromosome segregation during meiosis is of paramount importance to human health. The synaptonemal complex (SC) is a zipper-like structure ubiquitously present during meiosis from yeast to humans where it assembles between homologous chromosomes stabilizing homologous pairing interactions and promoting interhomolog crossover formation. However, despite its importance for key events required for accurate chromosome segregation during meiosis, the mechanisms regulating chromosome synapsis are not well understood in any organism. Moreover, studies focused on the post-translational regulation of proteins forming this structure are uncovering novel roles for the SC, linking it to the regulation of DSB formation and crossover designation. These recent findings further underscore the importance of this structure and of uncovering the roles it plays during meiosis. 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 molecular targets, place us in an ideal position to understand the regulation of chromosome synapsis and the roles exerted by the SC during meiosis. Here we propose two integrated aims to address these critical issues.
Aim 1 will address how ATM/ATR-mediated phosphorylation of SYP-4, a central region component of the SC, regulates SC dynamics, DNA double-strand break (DSB) repair, and crossover frequency and distribution.
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. We will also investigate the functional conservation shared between GRAS-1 and mammalian GRASP and CYTIP proteins, through combined studies in C. elegans and mice. These studies will shed new light on our understanding of the mechanisms regulating chromosome synapsis and the roles of the SC. Our studies are expected to impact multiple fields of tremendous relevance to human health including chromosome dynamics, the study of post-translational modifications, and regulation of macromolecular structures. Taken together, this application will provide significant new insights into the molecular mechanisms regulating accurate chromosome segregation during meiosis.

Public Health Relevance

Meiosis is a specialized cell division program that is essential for the formation of both eggs and sperm and therefore critically important for human reproductive health. Errors during meiosis are a leading cause of miscarriages, infertility and birth defects such as Down syndrome in humans. This application will investigate the regulation and the roles of the synaptonemal complex, a structure required for promoting accurate meiotic chromosome segregation in most organisms from yeast to humans, thereby laying the foundation for the development of effective preventive strategies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Gindhart, Joseph G
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Harvard Medical School
Schools of Medicine
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