DESCRIPTION (provided by applicant): Germ cells are specialized cells that undergo mitotic proliferation followed by meiosis and cellular differentiation to generate haploid gametes for sexual reproduction. Errors in human germ cells are quite common and result in a high frequency of spontaneous abortions and aneuploid progeny (e.g., Down, Turner and Klinefelter's Syndrome). Surprisingly, checkpoint control appears to be less efficient in the human female germ line;it has been proposed that this is one reason for the high frequency of defects associated with human female gametes. Here, we propose to take advantage of the unique structural organization of the Caenorhabditis elegans germ line, the molecular genetics of the system, and the high degree of conservation with genes and pathways in humans to determine the molecular basis for differential germ-line checkpoint function between the sexes. To tackle this important problem, we will use a multi-pronged approach that relies on the strengths of C. elegans as a model for investigating sex-specific germ-line checkpoint function. To that end, we will compare the surveillance mechanisms in operation in the female and male germ lines, and determine how males selectively sense and respond to damage in proliferating germ cells by analyzing known checkpoint mutants, examining the activation state of checkpoint proteins, and by identifying new checkpoint genes. We will determine how males prevent checkpoint-activated germ-line apoptosis and whether such absence leads to a high incidence of aneuploid gametes by monitoring the status of checkpoint and apoptotic proteins and examining the viability of progeny from reciprocal crosses when meiosis is impaired in only one of the sexes. Finally, we will determine how meiotically-induced double strand breaks are repaired on a single X chromosome without eliciting a checkpoint response by monitoring the loading and disassembly of chromosomal axis and central region components of the synaptonemal complex on the male X, probing the relationship between chromatin structure and checkpoint activation, and identifying the molecular machinery that prevents the single X from eliciting a checkpoint response. An understanding of this process in the genetically tractable worm system may provide insight into why human female meiosis has less efficient checkpoint control, contributing to the high rate of errors. These studies will also provide new and important information on general mechanisms of checkpoint control, processes in which defects are central to the developmental of human cancers. PUBLIC HEALTH RELEVANCE: Germ cells form egg and sperm for sexual reproduction. Our studies are aimed at understanding how errors arise during this process. In humans, such errors result in infertility, pregnancy loss and birth defects such as Down Syndrome.
|Effective start/end date||9/17/09 → 8/31/12|
- National Institutes of Health: $240,669.00
- National Institutes of Health: $239,915.00
- Biochemistry, Genetics and Molecular Biology(all)