In multicellular organisms it is crucial that cell growth and division be coordinated with developmental events. Recent advances have defined much of the regulatory circuitry that acts intrinsically to control transitions through the cell cycle. This makes it possible to build on this foundation to elucidate how developmental signals affect the cell cycle, Identification of regulatory genes affecting cell proliferation in response to developmental cues will have significant implications for understanding the causes of cancer. Drosophila is an ideal model organism in which to investigate this important question. The organism modifies its cell- cycle extensively during development, it is possible to identify mutants with cell cycle defects, and the genome project permits a rapid transition between recovering a mutant and isolating the responsible protein. The long-term objectives are to define the regulation of the meiotic cell cycle during oogenesis, fertilization, and the early cell cycles of embryogenesis. In Drosophila the mature oocyte is arrested at metaphase I of meiosis. There is an activation event, independent of fertilization, as the egg passes through the uterus that causes the completion of the meiotic divisions. Fertilization is required for the initiation of embryonic divisions, rapid cycles in which S phase alternates with mitosis without intervening gap phases. These S-M cycles of early embryogenesis differ from archetypical mitotic cycles in being controlled postranscriptionally, being nuclear divisions that occur in a shared cytoplasm, and as a result requiring localized activation and degradation of cell cycle regulators. The PAN GU (PNG) protein kinase is required specifically to promote mitosis and limit DNA replication during the S-M cycles. It is in complex with the PLUTONIUM (PLU) protein that is essential also to regulate these cycles. These proteins, together with the product of the giant nuclei (gnu) gene, are needed to maintain adequate levels of mitotic Cyclin proteins. The mechanism by which PNG, PLU, and GNU control Cyclin proteins and thus permit mitosis will be defined. Substrates of the PNG kinase will be identified, and the regulation of PNG and PLU determined. In vertebrates the mos oncogene is crucial to maintain metaphase arrest during meiosis in oocytes. A candidate Drosophila mos gene has been identified; its role during meiosis will be delineated. Because only a limited number of genes regulating the meiotic cell cycle, egg activation, and the early S-M embryonic cycles have been identified, a genetic screen will be carried out to recover additional control genes for these developmental changes in the cell cycle.
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