During the development of an organism, most tissues achieve a predictable size during development. The mechanisms that regulate the growth, proliferation and survival of individual cells in a spatiotemporal manner to achieve the final size and shape of the organ are poorly understood. Our laboratory has used a genetic approach in the fruit fly Drosophila melanogaster to identify genes that regulate cell proliferation and organ size. Among the genes characterized in previous funding cycles include several components of the Hippo pathway, archipelago, which encodes a ubiquitin ligase that targets Cyclin E and Myc for degradation and the Tsc1 and Tsc2 genes. In addition to regulating growth during development, these genes are of interest because their human orthologs are mutated in several types of cancer. We have recently found that the spitfire gene, which encodes a ubiquitin ligase, functions as a negative regulator of tissue growth and regulates the levels of the protocadherin Fat at the cell surface. Furthermore Spitfire and Fat appear to co-localize at the apical membrane and in a population of vesicles. We propose to elucidate the mechanism by which Spitfire regulates Fat localization and function. This will be achieved by identifying substrates of Spitfire using approaches that utilize mass spectrometry as well as by conducting genetic screens aimed at identifying regulators and effectors of Spitfire. We will also test whether Spitfire regulates other signaling pathways. We have also found that differences in expression levels of the autophagy regulator Atg2 between neighboring cells can influence tissue growth and cell survival near the clonal boundary. We will determine whether this phenomenon is due to a role for autophagy in cell-competition or similar process or, alternatively, whether a subset of Atg genes has a role in regulating cell proliferation and survival via an autophagy-independent pathway.
The precise regulation of cell growth, cell division and cell 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.
|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, TÃ¢nia; 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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