Human infertility and complications of reproductive processes have devastating social and monetary costs. We are attempting to identify genes necessary for fertility by studying mammalian meiosis using chemical mutagenesis, expression profiling, and immunocytochemistry in the mouse. For meiosis to succeed a complicated series of processes must occur including cell cycle progression, recombination, chromosome segregation and cell division. Phenotype-driven mutagenic screens have generated the mutation mei4. mei4 causes male and female sterility by disrupting gametogenesis during meiosis. Meiosis in mei4/mei4 homozygotes fails to complete due to a lack of recombination. While other DNA repair proteins such as Rad51 localize normally to meiotic chromosomes, the mismatch repair protein Mlh1 fails to load onto meiotic chromosomes during prophase I of meiosis in mei4/mei4 animals. We have identified the causative mutation behind the mei4 phenotype in a putative E3 ligase that functions to regulate cyclin degradation. This application proposes to characterize the mutant mei4 allele in the context of meiotic DNA repair and cell cycle biology. The role of mei4 in DNA mismatch repair and cell cycle progression will be elucidated via the following specific aims and strategies: (1) mRNA and protein expression profiling, (2) in vitro, in situ, and in vivo protein-protein interaction studies, (3) immunocytochemistry of protein constituents at recombination sites. This work has significant health relatedness as several of the mismatch repair proteins found to function in meiosis are also associated with hereditary non-polyposis colorectal cancer (HNPCC). E3 ligases and their substrates have been implicated in several cancers, including inherited breast cancer, and also in neurodegenerative disorders. Lastly, aneuploidy is a major source of birth defects resulting from non- disjunction or premature separation of meiotic chromosomes. mei4 has a severe meiotic aneuploid phenotype and thus its characterization will address potential causes of clinical aneuploidy and birth defects. The characterization of mei4 will not only contribute to our understanding of the basic molecular biology of meiosis but also increase our knowledge of important human health issues. ? ? ?
| Schimenti, Kerry J; Feuer, Sky K; Griffin, Laurie B et al. (2013) AKAP9 is essential for spermatogenesis and sertoli cell maturation in mice. Genetics 194:447-57 |
| Ward, Jeremy O; Reinholdt, Laura G; Motley, William W et al. (2007) Mutation in mouse hei10, an e3 ubiquitin ligase, disrupts meiotic crossing over. PLoS Genet 3:e139 |
