The overall goal of this proposal is to determine the role of the dual-specificity phosphatase Cdc14 during mammalian meiosis. Meiosis is the process by which a diploid precursor cell produces haploids and it is linked to species-specific differentiation programs that generate gametes. Cdc14 is highly conserved throughout evolution and is a critical mitotic cell-cycle regulator in all organisms studied to date. In budding yeast, Cdc14 mutants are unable to properly complete the first meiotic division where homologs are segregated. Mistakes in meiosis I are linked to nondisjunctions and chromosomal anomalies in humans. Higher eukaryotes contain 2 Cdc14 proteins, Cdc14a and Cdc14b, and the functions of both will be explored in this proposal.
The specific aims of this proposal are to 1) test the hypothesis that Cdc14a and Cdc14b are required for meiosis in the mouse oocyte using an RNA interference (RNAi) approach, 2) test the hypothesis that over-expression of Cdc14a and Cdc14b will alter meiosis in the mouse oocyte and develop a method to image living oocytes and 3) identify domains within the CDC14 proteins that regulate their subcellular localization during meiosis by mutagenesis. Meiosis is the process that generates eggs in females and sperm in males. Female meiosis is highly error- prone in humans as approximately 20% of all eggs contain abnormal chromosome numbers that, when fertilized by sperm, leads to spontaneous abortions, stillbirths and, in live births, developmental diseases like Down Syndrome. Exploring how the meiotic cell cycle is regulated is key to gaining an understanding of how errors in the segregation of DNA are linked to human chromosomal disorders. ? ? ?
