Meiosis is the specialized cell division whereby one diploid cell divides twice to produce four haploid spores or gametes. Meiotic defects lead to sterility, reduced fertility and aneuploidy. Aneuploidy is a leading cause of miscarriage and common developmental disorders, like Down ?s syndrome. Because of these devastating effects, meiotic checkpoints help to arrest meiosis in response to defects that cause aneuploidy. For example, in the yeast, Saccharomyces cerevisiae, substantial evidence shows that recombination defects cause a meiotic arrest, which is dependent on the DNA damage checkpoint protein, RAD24. Because in mice, meiosis must operate within the context of a multi-cellular and sexually dimorphic system, it is likely that a large number of novel mammalian meiotic genes exist to accommodate this system. Using both comparative and forward genetics approaches, this goal of this proposal is to initially characterize a meiotic checkpoint in mice, where significantly less is known about these pathways. To achieve this goal, the function of a putative meiotic checkpoint protein, Rad24, will be removed. Double mutants will be created to see if the meiotic arrests found in a putative recombination mutant and in a novel meiotic mutant, are alleviated by the removal of Rad24 function. If so, this will show that Rad24 is a key meiotic checkpoint protein in mice. In addition, this will provide information as to the types of defects that trigger meiotic arrest in mice. Finally, a new, potentially meiotic mutation, Mei5, which may cause a meiotic defect that escapes detection by meiotic checkpoint mechanisms, will be phenotypically characterized and genetically mapped.
| 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 |
| Reinholdt, Laura G; Munroe, Robert J; Kamdar, Sonja et al. (2006) The mouse gcd2 mutation causes primordial germ cell depletion. Mech Dev 123:559-69 |
| Ward, Jeremy O; Reinholdt, Laura G; Hartford, Suzanne A et al. (2003) Toward the genetics of mammalian reproduction: induction and mapping of gametogenesis mutants in mice. Biol Reprod 69:1615-25 |
