Aneuploidy is a significant factor contributing to human fetal wastage and birth defects; the primary cause of aneuploidy is meiotic error during formation of the gametes. Thus successful completion of meiotic processes ensures that gametes have the correct, haploid, chromosomal content. The central problems addressed in this proposal are how mouse spermatocytes get into and get out of meiotic metaphase I (MI). These critical steps in spermatogenesis not only determine the fidelity of the chromosome content of sperm cells, but also result in expansion of the germ-cell population. In the past project period, basic elements of cell-cycle regulation during spermatogenic meiosis were defined. New experiments will build from this foundation in two ways. The first will be by experimental analysis of cellular processes leading to chromosome condensation and alignment. The second will be by perturbing cell cycle regulation, calling into play cell cycle checkpoint mechanisms, an experimental strategy that will provide information about mechanisms that govern meiotic progress and success. Checkpoint responses will be elicited by a variety of experimental treatments and genetic conditions, including induced DNA damage and chromosomal aberrations that give rise to malsegregation during the meiotic division phase.
Aims 1 -3 address how the spermatocyte gets into meiotic metaphase: chromosome condensation and checkpoint regulation.
Aims 4 -5 address how the spermatocyte exits the first meiotic metaphase: the basic events and the role of spindle checkpoint responses to chromosome aberrations. Taken together, these experiments will define parameters of cell cycle transitions that are important for accurate chromosome segregation and test the hypothesis that, in contrast to females, males have effective checkpoints that monitor meiotic progress and govern entry to and exit from meiotic metaphase I.
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