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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072551-13
Application #
9534686
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Melillo, Amanda A
Project Start
2005-08-01
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
Ferrandiz, Nuria; Barroso, Consuelo; Telecan, Oana et al. (2018) Spatiotemporal regulation of Aurora B recruitment ensures release of cohesion during C. elegans oocyte meiosis. Nat Commun 9:834
Gao, Jinmin; Colaiácovo, Monica P (2018) Zipping and Unzipping: Protein Modifications Regulating Synaptonemal Complex Dynamics. Trends Genet 34:232-245
Tzur, Yonatan B; Winter, Eitan; Gao, Jinmin et al. (2018) Spatiotemporal Gene Expression Analysis of the Caenorhabditis elegans Germline Uncovers a Syncytial Expression Switch. Genetics 210:587-605
Nadarajan, Saravanapriah; Lambert, Talley J; Altendorfer, Elisabeth et al. (2017) Polo-like kinase-dependent phosphorylation of the synaptonemal complex protein SYP-4 regulates double-strand break formation through a negative feedback loop. Elife 6:
Nottke, Amanda C; Kim, Hyun-Min; Colaiácovo, Monica P (2017) Wrestling with Chromosomes: The Roles of SUMO During Meiosis. Adv Exp Med Biol 963:185-196
Nadarajan, Saravanapriah; Mohideen, Firaz; Tzur, Yonatan B et al. (2016) The MAP kinase pathway coordinates crossover designation with disassembly of synaptonemal complex proteins during meiosis. Elife 5:e12039
Gao, Jinmin; Barroso, Consuelo; Zhang, Pan et al. (2016) N-terminal acetylation promotes synaptonemal complex assembly in C. elegans. Genes Dev 30:2404-2416
Kim, Hyun-Min; Colaiácovo, Monica P (2016) CRISPR-Cas9-Guided Genome Engineering in C. elegans. Curr Protoc Mol Biol 115:31.7.1-31.7.18
Kim, Hyun-Min; Colaiácovo, Monica P (2015) New Insights into the Post-Translational Regulation of DNA Damage Response and Double-Strand Break Repair in Caenorhabditis elegans. Genetics 200:495-504
Mendes, Tasha K; Novakovic, Stevan; Raymant, Greta et al. (2015) Investigating the role of RIO protein kinases in Caenorhabditis elegans. PLoS One 10:e0117444

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