During meiotic prophase, chromosomes undergo dramatic structural changes: They condense, pair and align with their homologous partners, assemble synaptonemal complexes, undergo recombination, and reorganize again to reveal chiasmata, structures that hold homologs together until anaphase I and direct the orientation of linked homolog pairs (bivalents) on the meiosis I spindle. These events are of central importance to sexually reproducing organisms, since they are required to direct the orderly segregation of homologous chromosomes at meiosis I, the specialized cell division that allows diploid organisms to generate haploid gametes. Failure to execute these events correctly leads to chromosomal aneuploidy, one of the leading causes of miscarriages and birth defects in humans. Our goal is to understand how meiosis-specific chromosome organization is established, maintained and remodeled to bring about successful segregation of homologous chromosomes. We are approaching this problem using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining robust cytological, genetic and genomic approaches in a single experimental system, and in which the events under study are particularly accessible. One major goal is to investigate the assembly, regulation and dynamics of the synaptonemal complex (SC) and its relationships to homolog pairing and meiotic progression. We will capitalize on advances in microscopic imaging, experimental advantages of the system, and knowledge, tools and resources generated during the prior period to conduct live imaging of SC assembly and to evaluate dynamics of meiotic prophase chromosome structures. We will also investigate the function of a key regulator of meiotic events in coordinating homolog pairing and SC assembly, and will exploit our ability to visualize SCs in live worms to identify additional components of a regulatory network that couples SC assembly/disassembly with progression of other meiotic events. A second major goal is to use Hi-C technology to investigate how DNA is organized in homologously paired meiotic prophase chromosomes, taking advantage of features of the C. elegans system that make it well- suited to exploiting the potential of this emerging technology to provide novel insights regarding meiotic chromosome organization, particularly in the context of homolog pairing and alignment.
The proposed research will increase our understanding of the basic mechanisms that promote and ensure the faithful inheritance of chromosomes. The work is highly relevant to human health, as errors in chromosome inheritance are one of the leading causes of miscarriages and birth defects and are also a major factor contributing to the development and progression of cancer. The plan will focus on understanding how key events are coordinated during the meiotic program, how chromosomes are organized in 3D space, and how these features contribute to successful inheritance of genomes.
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