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, the linkages that hold homologs together until anaphase I. 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 dynamic reorganization of chromosome structure during meiotic prophase contributes to successful segregation of homologous chromosomes, particularly in the context of oocyte meiosis where the chromosomes are thought to play a central role in nucleating formation of the meiotic spindle. We are approaching this problem using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining robust genetic, genomic and cytological approaches in a single experimental system, and in which the events under study are particularly accessible. We will investigate how features of meiotic chromosome structure generated during meiotic prophase contribute to chromosome and spindle dynamics at the oocyte meiosis I division, using high resolution imaging of both fixed and live specimens and exploiting our collection of meiotic mutants and our ability to manipulate karyotype to alter meiotic chromosome organization. We will use an integrated genetic, cytological, biochemical and proteomics approach to investigate how known meiotic machinery components coordinate homolog pairing and SC assembly to ensure that meiotic structures develop appropriately, linking axes of coaligned homologous chromosomes. We will use tools that monitor the status of pairing in live worms as the basis of screens designed to identify pairing machinery components, as a route toward molecular definition of cis-acting chromosomal features that stabilize pairing, and as a means to perform live imaging of pairing dynamics. ? ?
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