Our goal is to understand both mammalian meiotic recombination and the checkpoints that monitor it. Recombination generates physical connections between homologous chromosomes that are essential for accurate segregation. If recombination is altered, chromosome segregation is affected, and gamete aneuploidy results. The molecular mechanisms of recombination and the processes that protect against recombination errors are not well understood. Mouse is ideal for these studies because of extensive conservation of relevant molecular processes with humans.
Specific aims are to: 1. Characterize crossover homeostasis in mouse. In yeast, crossover numbers are maintained even when DSB frequencies are decreased (""""""""crossover homeostasis""""""""). The same process may operate in mouse. This hypothesis will be tested by cytological and molecular analysis of recombination in male and female animals with reduced dosage of Spo11, the gene encoding the protein that initiates recombination. 2. Define the roles of ATM in meiotic recombination. The checkpoint kinase ATM is required for repair of meiotic DMA breaks and for crossover control. Behaviors of recombination proteins and structures of recombination products will be determined in mice lacking ATM. 3. Define the functions of Spo11 splicing isoforms. Multiple splice variants of mouse and human Spo11 have been described. The functions of the encoded proteins are not known. This issue will be addressed through characterization of mice carrying transgenes or targeted mutations that express individual isoforms. 4. To determine the role of TRIP13 (PCH2) in monitoring chromosome synapsis defects. Recent studies in yeast and nematode demonstrated the existence of a chromosome synapsis checkpoint that is distinct from the recombination checkpoint. We will test whether a mouse homolog of the synapsis checkpoint protein PCH2 functions in a similar pathway in mammalian meiosis. Relevance: Abnormal chromosome numbers in eggs or sperm cause developmental disabilities or spontaneous abortion. These abnormalities often arise because of improper separation of chromosomes caused by defects in meiotic homologous recombination. This project will address fundamental questions about how mammals control meiotic recombination and respond when there are problems. ? ? ?
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