This project's goal is to understand the molecular mechanisms controlling different types of cell cycles during development of Drosophila, and to discover how genetic programming of these mechanisms coordinates the cell cycle with morphogenesis and differentiation.
Specific aims are: l) To determine how transcription of the cell cycle control gene, string (cdc25) is regulated. Patterns of mitoses in the postblastoderm embryo are directed by transient pulses of transcription of string, which encodes a phosphatase that activates the mitotic kinase, Cdc2. string appears to integrate pattern information in the embryo using a complex cis-regulatory region. We will use an enhancer/reporter strategy to map string 's regulatory region, and take advantage of existing selector-gene mutants to identify trans-regulators that interact with this region. 2) To determine how maternal cell cycle control is succeeded by zygotic control during Drosophila's """"""""midblastula transition."""""""" Recent experiments indicate that slowing of the cycle occurs by depletion of Cyclins, and that degradation of String protein terminates these cycles. We will test these ideas by genetic manipulations of levels of maternal Cyclins and String. We will also undertake a cytological and molecular analysis of Cyclin and String degradation mechanisms. 3) To isolate Drosophila mutants defective in the G1/S transition. Screens will be done for P-transposon and EMS-induced mutants that undergo first instar larval growth arrest, a predicted phenotype of Drosophila mutants defective in G 1/5 functions. In addition, F1 mosaic screens for mutants defective in cell proliferation will be performed. Secondary tests will identify genes required specifically for S phase initiation, and these will be cloned by plasmid rescue of P alleles.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics Study Section (GEN)
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Fred Hutchinson Cancer Research Center
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Kohlmaier, A; Fassnacht, C; Jin, Y et al. (2015) Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine. Oncogene 34:2371-84
Patel, Parthive H; Dutta, Devanjali; Edgar, Bruce A (2015) Niche appropriation by Drosophila intestinal stem cell tumours. Nat Cell Biol 17:1182-92
Doumpas, Nikolaos; Ruiz-Romero, Marina; Blanco, Enrique et al. (2013) Brk regulates wing disc growth in part via repression of Myc expression. EMBO Rep 14:261-8
Zielke, Norman; Edgar, Bruce A; DePamphilis, Melvin L (2013) Endoreplication. Cold Spring Harb Perspect Biol 5:a012948
Edgar, Bruce A (2012) Intestinal stem cells: no longer immortal but ever so clever.... EMBO J 31:2441-3
Jiang, Huaqi; Edgar, Bruce A (2012) Intestinal stem cell function in Drosophila and mice. Curr Opin Genet Dev 22:354-60
Zielke, Norman; Kim, Kerry J; Tran, Vuong et al. (2011) Control of Drosophila endocycles by E2F and CRL4(CDT2). Nature 480:123-7
O'Keefe, David D; Edgar, Bruce A; Saucedo, Leslie J (2011) EndoGI modulates Notch signaling and axon guidance in Drosophila. Mech Dev 128:59-70
Jiang, Huaqi; Grenley, Marc O; Bravo, Maria-Jose et al. (2011) EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell Stem Cell 8:84-95
Jiang, Huaqi; Edgar, Bruce A (2009) EGFR signaling regulates the proliferation of Drosophila adult midgut progenitors. Development 136:483-93

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