The experiments described in this proposal are aimed at characterizing the mechanisms that regulate the size of individual cells as well as the size of whole organs. We have conducted a genetic screen in the fruit fly, Drosophila, and identified mutations in at least sixteen different genes that result either in increased cell size or an increase in the overall size of the eye. In the previous funding period, we showed that the Drosophila orthologs of the tuberous sclerosis genes, function to restrict cell growth in vivo. We have also identified and characterized several novel regulators of cell and tissue growth including Archipelago as well as a complex composed of the Salvador, Warts and Hippo proteins. In this application, experiments are proposed to characterize several pathways that regulate tissue growth but that are still poorly understood. Our laboratory has recently shown that the HMG-box protein Capicua functions downstream of the EGF receptor and Ras to regulate cell growth.
Specific Aim 1 details experiments that will help define the precise role of Capicua in this pathway. First, experiments are proposed that wil investigate the mechansim by which activtton of the Egfr/Ras pathway downregulates Capicua levels. Second, using oligonucleotide microarrays and chromatin immunopreciptiation, we will identify genes whose expression is directly regulated by Capicua.
Specific Aim 2 proposes an analysis of mutations that increase tissue growth by a non-cellautonomous mechanism. In these mutants, the mutant cells grow poorly but their presence leads to the overgrowth of adjacent wild-type tissue. Our experiments will help define the mechansim by which this overgrowth occurs by characterizing the nature of the growth promoting signals produced by the mutant cells. Together, these studies will help us understand how growth is regulated in vivo during the normal development of an organism. Our findings will also be relevant for understanding the perturbed growth that occurs in human cancers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 1 Study Section (DEV)
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Anderson, Richard A
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University of California Berkeley
Schools of Arts and Sciences
United States
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Hariharan, Iswar K; Serras, Florenci (2017) Imaginal disc regeneration takes flight. Curr Opin Cell Biol 48:10-16
Hariharan, Iswar K (2016) Size regulation blossoms in Kobe. Development 143:2691-5
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

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