The precise patterns of embryonic cell division contribute to normal morphogenesis and reflect tight control of cell proliferation in metazoans. Identification of the mechanisms of this control should illuminate aspects of embryonic patterning and of diseases resulting from defects in the control of cell proliferation. Cell cycle regulators and the developmental programs that influence their activity are widely conserved. However, development does not simply impose controls on a standard cell cycle. It changes the very nature of the cycle, deleting and adding steps by changing the levels of fundamental cell cycle components. Drosophila provides a powerful model system for analyses of these developmental controls: in addition to genetic, molecular and developmental tools, many characterized cell cycle regulators are available in this organism. Cycles 1-7 forgo all familiar controls. Only exit from mitosis seems regulated, perhaps by cytoskeletal influences on cyclin B degradation. The importance of cyclin degradation will be tested by introduction of non-destructible mutants of cyclin, and cyclin stability will be examined in mutants defective in arrest at the first mitosis. During cycles 1-16, progress to S phase is limited only by a requirement to pass through mitosis. The DNA is thought to gain the license to replicate once each time it passes through mitosis. We will test the roles of candidate licensing factor genes cloned by homology to yeast replication genes. Progress to mitosis is usually blocked if DNA synthesis is arrested. This S phase checkpoint control involves inhibitory phosphorylation of Cdc2, and becomes operative only at cycle 14 when this inhibitory phosphorylation first occurs. We will examine regulation of a recently cloned kinase that is apparently responsible for this inhibitory phosphorylation. Rapid cell cycling inhibits transcription in early embryos, and cycle lengthening appears to be a key regulator of transcription. We will test whether the mitotic Cdc2 kinase directly inhibits transcription by phosphorylating RNA polymerase, and whether passage of a replication fork interferes with ongoing transcription. In cycle 14, another feature of cell cycle control becomes evident: the orientation of cell division planes is regulated. We will identify genes responsible for re-orienting division planes in stereotyped patterns.
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