This proposal is to continue ongoing studies of the cell growth control in Drosophila. We have three long-term objectives: 1) to define the cell-intrinsic mechanisms that control cell mass increase (growth); 2) to determine how cell cycle progression is coordinated with growth; and 3) to learn how patterned growth is regulated during organ morphogenesis.
Four specific aims are proposed.
In Aim 1 we characterize the molecular, cellular, and developmental functions of rheb, a conserved G-protein that appears to function in the insulin signaling/tuberous sclerosis (TSC)/target of rapamycin (TOR) pathway, which governs nutritionally regulated cell growth. Under this aim we also ask whether the control of ribosomal RNA synthesis is used as a means of nutritional or developmental growth control.
Aim 2 proposes two forward genetic screens. One screen will select for loss-of-function suppressors of rheb-mediated growth, and should identify downstream effectors in the insulin/TSC/TOR pathway. The other screen is for genes that, when over-expressed, cause clonal overgrowth in the developing eye; this should isolate several classes of genes that promote cell proliferation.
Aim 3 proposes molecular tests to determine how cellular growth regulates Cyclin E and E2F to drive G1/S transitions in the cell cycle.
Aim 4 applies the yield of previous aims to the problem of development. We employ epistasis tests using known growth regulators, as well as gene expression profiling, to define growth-regulatory targets of the TGF-beta/BMP4 homolog, dpp, and the homeobox transcription factor, Ubx, which orchestrate patterned growth in the developing fly wing. We test the roles, in developmentally regulated growth, of dMyc, rRNA synthesis, components of the insulin/TOR signaling pathway, and others. The project as a whole makes extensive use of genetic epistasis tests, mosaic analysis, quantitative cytological assays of growth and proliferation, gene mapping, and gene expression profiling. This work will define new genes and mechanisms involved in growth control and should impact general paradigms in cell and developmental biology. It has relevance to medical conditions involving cell and tissue growth including cancer diagnosis and therapy, regeneration, wound healing, diabetes and other metabolic diseases.
| 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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