This project is aimed at understanding the genetic pathways that tissue growth and organ size in vivo. Previous studies in our laboratory have utilized a screen that utilizes genetic mosaics generated in the developing Drosophila eye to identify mutations that result in tissue overgrowth. Many of the mutations that have been identified in the screen have been characterized during previous funding periods of this grant. In this proposal, the first two Specific Aims detail experiments to characterize two loci that were identified in the screen of the X-chromosome: ovo and HK115.
Aim 1 describes a strategy for identifying the open reading frame that is mutated in the HK115 mutants and experiments to determine how HK115 regulates tissue growth and apoptosis.
Aim 2 outlines studies for characterizing the pathway by which ovo, which encodes a transcription factor regulates growth and cell cycle progression.
Aims 3 and 4 address a poorly understood phenomenon known as cell competition by which cells are able to kill adjacent cells that grow more slowly. A novel screen has been developed to identify supercompetitors - mutations that enable mutant cells to kill their wild-type neighbors. Mutations in crumbs, a regulator of apicobasal polarity were identified in the screen.
Aim 3 describes an approach to determine how crumbs functions with respect to cell competition.
Aim 4 consists of a broad strategy, including a new genetic screen, for identifying and characterizing additional genes that regulate cell competition. These studies are likely to provide valuable insights into how growth is regulated during development as well as the growth abnormalities that occur during the development of tumors.

Public Health Relevance

The precise regulation of cell growth, cell division and survival are necessary for the proper development of an organism. Perturbations of these processes can result in birth abnormalities and cancer. This proposal describes a genetic approach, using the fruit fly, to improve our understanding the mechanisms that regulate tissue growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061672-12
Application #
8323352
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Gaillard, Shawn R
Project Start
2000-08-01
Project End
2013-12-31
Budget Start
2012-09-01
Budget End
2013-12-31
Support Year
12
Fiscal Year
2012
Total Cost
$294,618
Indirect Cost
$98,598
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Bosch, Justin A; Sumabat, Taryn M; Hariharan, Iswar K (2016) Persistence of RNAi-Mediated Knockdown in Drosophila Complicates Mosaic Analysis Yet Enables Highly Sensitive Lineage Tracing. Genetics 203:109-18
Bosch, Justin A; Tran, Ngoc Han; Hariharan, Iswar K (2015) CoinFLP: a system for efficient mosaic screening and for visualizing clonal boundaries in Drosophila. Development 142:597-606
Hariharan, Iswar K (2015) Organ Size Control: Lessons from Drosophila. Dev Cell 34:255-65
Bosch, Justin A; Sumabat, Taryn M; Hafezi, Yassi et al. (2014) The Drosophila F-box protein Fbxl7 binds to the protocadherin fat and regulates Dachs localization and Hippo signaling. Elife 3:e03383
Kanda, Hiroshi; Nguyen, Alexander; Chen, Leslie et al. (2013) The Drosophila ortholog of MLL3 and MLL4, trithorax related, functions as a negative regulator of tissue growth. Mol Cell Biol 33:1702-10
Worley, Melanie I; Setiawan, Linda; Hariharan, Iswar K (2013) TIE-DYE: a combinatorial marking system to visualize and genetically manipulate clones during development in Drosophila melanogaster. Development 140:3275-84
Hariharan, Iswar K (2012) How growth abnormalities delay ""puberty"" in Drosophila. Sci Signal 5:pe27
Harvey, Kieran F; Hariharan, Iswar K (2012) The hippo pathway. Cold Spring Harb Perspect Biol 4:a011288
Hafezi, Yassi; Bosch, Justin A; Hariharan, Iswar K (2012) Differences in levels of the transmembrane protein Crumbs can influence cell survival at clonal boundaries. Dev Biol 368:358-69
Reis, Tânia; Van Gilst, Marc R; Hariharan, Iswar K (2010) A buoyancy-based screen of Drosophila larvae for fat-storage mutants reveals a role for Sir2 in coupling fat storage to nutrient availability. PLoS Genet 6:e1001206

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