Control of cell number in developing retina

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DESCRIPTION (provided by applicant): 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.