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.
|Schvarzstein, Mara; Pattabiraman, Divya; Libuda, Diana E et al. (2014) DNA helicase HIM-6/BLM both promotes MutS?-dependent crossovers and antagonizes MutS?-independent interhomolog associations during caenorhabditis elegans meiosis. Genetics 198:193-207|
|Labrador, Leticia; Barroso, Consuelo; Lightfoot, James et al. (2013) Chromosome movements promoted by the mitochondrial protein SPD-3 are required for homology search during Caenorhabditis elegans meiosis. PLoS Genet 9:e1003497|
|Schvarzstein, Mara; Pattabiraman, Divya; Bembenek, Joshua N et al. (2013) Meiotic HORMA domain proteins prevent untimely centriole disengagement during Caenorhabditis elegans spermatocyte meiosis. Proc Natl Acad Sci U S A 110:E898-907|
|Nabeshima, Kentaro; Mlynarczyk-Evans, Susanna; Villeneuve, Anne M (2011) Chromosome painting reveals asynaptic full alignment of homologs and HIM-8-dependent remodeling of X chromosome territories during Caenorhabditis elegans meiosis. PLoS Genet 7:e1002231|
|Schvarzstein, Mara; Wignall, Sarah M; Villeneuve, Anne M (2010) Coordinating cohesion, co-orientation, and congression during meiosis: lessons from holocentric chromosomes. Genes Dev 24:219-28|
|Hayashi, Michiko; Mlynarczyk-Evans, Susanna; Villeneuve, Anne M (2010) The synaptonemal complex shapes the crossover landscape through cooperative assembly, crossover promotion and crossover inhibition during Caenorhabditis elegans meiosis. Genetics 186:45-58|
|Gent, Jonathan I; Schvarzstein, Mara; Villeneuve, Anne M et al. (2009) A Caenorhabditis elegans RNA-directed RNA polymerase in sperm development and endogenous RNA interference. Genetics 183:1297-314|
|Wignall, Sarah M; Villeneuve, Anne M (2009) Lateral microtubule bundles promote chromosome alignment during acentrosomal oocyte meiosis. Nat Cell Biol 11:839-44|
|Martinez-Perez, Enrique; Schvarzstein, Mara; Barroso, Consuelo et al. (2008) Crossovers trigger a remodeling of meiotic chromosome axis composition that is linked to two-step loss of sister chromatid cohesion. Genes Dev 22:2886-901|
|Smolikov, Sarit; Eizinger, Andreas; Schild-Prufert, Kristina et al. (2007) SYP-3 restricts synaptonemal complex assembly to bridge paired chromosome axes during meiosis in Caenorhabditis elegans. Genetics 176:2015-25|
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