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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM037193-09
Application #
2178709
Study Section
Molecular Biology Study Section (MBY)
Project Start
1986-07-01
Project End
1998-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Yuan, Kai; Seller, Charles A; Shermoen, Antony W et al. (2016) Timing the Drosophila Mid-Blastula Transition: A Cell Cycle-Centered View. Trends Genet 32:496-507
Yuan, Kai; O'Farrell, Patrick H (2016) TALE-light imaging reveals maternally guided, H3K9me2/3-independent emergence of functional heterochromatin in Drosophila embryos. Genes Dev 30:579-93
Yuan, Kai; O'Farrell, Patrick H (2015) Cyclin B3 is a mitotic cyclin that promotes the metaphase-anaphase transition. Curr Biol 25:811-816
O'Farrell, Patrick H (2015) Growing an Embryo from a Single Cell: A Hurdle in Animal Life. Cold Spring Harb Perspect Biol 7:
Farrell, Jeffrey A; O'Farrell, Patrick H (2014) From egg to gastrula: how the cell cycle is remodeled during the Drosophila mid-blastula transition. Annu Rev Genet 48:269-94
Yuan, Kai; Shermoen, Antony W; O'Farrell, Patrick H (2014) Illuminating DNA replication during Drosophila development using TALE-lights. Curr Biol 24:R144-5
El Amine, Nour; Kechad, Amel; Jananji, Silvana et al. (2013) Opposing actions of septins and Sticky on Anillin promote the transition from contractile to midbody ring. J Cell Biol 203:487-504
Farrell, Jeffrey A; O'Farrell, Patrick H (2013) Mechanism and regulation of Cdc25/Twine protein destruction in embryonic cell-cycle remodeling. Curr Biol 23:118-26
Kechad, Amel; Jananji, Silvana; Ruella, Yvonne et al. (2012) Anillin acts as a bifunctional linker coordinating midbody ring biogenesis during cytokinesis. Curr Biol 22:197-203
Yuan, Kai; Farrell, Jeffrey A; O'Farrell, Patrick H (2012) Different cyclin types collaborate to reverse the S-phase checkpoint and permit prompt mitosis. J Cell Biol 198:973-80

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