Meiosis generates haploid gametes, such as sperm and eggs, from a diploid cell such that a diploid genome is restored upon fertilization. The proper segregation of chromosomes during the meiotic divisions relies on events in meiotic prophase, such as synapsis of homologous chromosomes and crossover recombination. Errors in chromosome segregation are usually fatal to the fertilized zygote but can also result in cancer predisposition or developmental disorders. In C. elegans, a meiotic checkpoint monitors homolog synapsis, independent of a DNA damage/recombination checkpoint, and activates apoptosis to avoid the generation of aneuploid gametes. This checkpoint depends on Pairing Centers (PCs), chromosome sites that act as sites for synapsis initiation. PCs promote synapsis by nucleating structures at the nuclear envelope to gain access to cytoplasmic microtubules and mobilize chromosomes. Since PCs mediate microtubule attachment and are regulatory platforms for checkpoints that monitor chromosome behavior, PCs have been compared to centromeres. Although the cytoskeletal-mediated mobilization of chromosomes is a common feature of meiotic prophase, its specific function during synapsis is not well understood. Our initial studies of this meiotic checkpoint have revealed that the monitoring and regulation of homolog synapsis are mechanistically linked: components of this checkpoint are also required to mediate synapsis. We have also uncovered a surprising connection between the synapsis checkpoint and the mitotic spindle checkpoint. Using a combination of genetic, biochemical and cytological approaches, we plan to further investigate this link between synapsis initiation, synapsis checkpoint activation and PC function. We will answer the following questions: 1) Do factors required for the synapsis checkpoint regulate PC movement to inhibit synapsis initiation? 2) What functions of MAD-1 and MAD-2 are required to regulate and monitor synapsis? 3) Does the conserved protein Shugoshin define a new pathway to regulate and monitor synapsis? Given that the mobilization of chromosomes during meiotic prophase is conserved, it is likely that our studies will provide important information about the regulation of synapsis even in systems that do not rely on PCs for synapsis.
/Relevance Homolog synapsis is essential for proper chromosome segregation during meiosis, the specialized cell division that gives rise to gametes, such as sperm and eggs. If a gamete has an incorrect number of chromosomes, the embryo that results from fertilization can be inviable or have birth defects. Thus, investigations of meiotic synapsis will reveal the mechanisms that ensure that gametes have the correct number of chromosomes and give rise to viable, healthy progeny.
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