Successful development of a functional eye requires not only cell-differentiation programs that specify various retina cell types, but also size-control mechanisms that determine the number of cells in the retina. My laboratory is taking molecular, genetic and biochemical approaches to understand the molecular mechanisms that specify retina cell number. Using the compound eye of Drosophila as an experimental model, my laboratory has recently identified a key signaling pathway that controls retina cell number by coordinately regulating cell proliferation and cell death. This pathway is defined by three tumor suppressor genes that normally negatively regulate retina cell number: hippo (hpo), salvador (sav) and warts (wts). Hpo, a Ser/Thr kinase, binds to and phosphorylates Sav, an adaptor protein containing WW and coiled-coil domains. Interactions between Hpo and Sav in turn potentiate the kinase activity of Hpo towards Wts. Inactivation of this pathway results in elevated transcription of the cell cycle regulator Cyclin E and the cell death inhibitor diap1, thus leading to increased proliferation and reduced apoptosis. Moreover, this pathway appears to play an evolutionarily conserved role in mammals. Here we propose three specific aims to further understand the function and regulation of the Hpo pathway in retina size-control. In the first specific aim, we will determine the molecular mechanisms by which the Hpo pathway regulates diap1 transcription by identifying the Hpo-responsive transcription factor and analyzing its mode of regulation. In the second specific aim, we will determine the cellular mechanism of the Hpo signal transduction pathway. In the third specific aim, we will use biochemical, yeast two-hybrid and genetic approaches to identify additional components of the Hpo pathway. Besides revealing basic mechanisms of eye development, our studies have general implications for the development of other tissues.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY015708-01
Application #
6808998
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Hunter, Chyren
Project Start
2004-08-01
Project End
2004-11-30
Budget Start
2004-08-01
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$29,483
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Physiology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Yu, Jianzhong; Pan, Duojia (2018) Validating upstream regulators of Yorkie activity in Hippo signaling through scalloped-based genetic epistasis. Development 145:
Zheng, Yonggang; Liu, Bo; Wang, Li et al. (2017) Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex. Cell Rep 21:3612-3623
Das, Arupratan; Fischer, Robert S; Pan, Duojia et al. (2016) YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing. J Biol Chem 291:6096-110
Liu, Bo; Zheng, Yonggang; Yin, Feng et al. (2016) Toll Receptor-Mediated Hippo Signaling Controls Innate Immunity in Drosophila. Cell 164:406-19
Chan, PuiYee; Han, Xiao; Zheng, Baohui et al. (2016) Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat Chem Biol 12:282-9
Deng, Hua; Wang, Wei; Yu, Jianzhong et al. (2015) Spectrin regulates Hippo signaling by modulating cortical actomyosin activity. Elife 4:e06567
Zheng, Yonggang; Wang, Wei; Liu, Bo et al. (2015) Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade. Dev Cell 34:642-55
Pan, Duojia (2015) YAPing Hippo Forecasts a New Target for Lung Cancer Prevention and Treatment. J Clin Oncol 33:2311-3
Ni, Lisheng; Zheng, Yonggang; Hara, Mayuko et al. (2015) Structural basis for Mob1-dependent activation of the core Mst-Lats kinase cascade in Hippo signaling. Genes Dev 29:1416-31
Chen, Qian; Zhang, Nailing; Xie, Rui et al. (2015) Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev 29:1285-97

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