Control of Cell Number in Developing Retina

Ut Southwestern Medical Center, Dallas TX

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Abstract

Project Summary / Abstract My long-term scientific goal is to understand the molecular mechanisms that specify retina cell number. Using the compound eye of Drosophila as an experimental model, my laboratory has discovered the Hippo pathway as a central mechanism underlying this process. The core of the Hippo pathway comprises a kinase cascade in which the Ste20 kinase Hippo (Hpo) phosphorylates and activates the NDR family kinase Warts (Wts). Wts, in turn, phosphorylates and inactivates the oncoprotein Yorkie (Yki) by excluding it from the nucleus, where it normally functions as a coactivator for the DNA-binding transcription factor Scalloped (Sd). Our research further established a critical role for the Hippo pathway in controlling organ size in mammals, underscoring the importance of Drosophila as a powerful model to discover universal developmental mechanisms. Despite recent progress in elucidating the molecular underpinnings of the Hippo signaling pathway, our understanding of this growth-regulatory pathway remains incomplete. In the current grant period, we have further advanced our mechanistic understanding of the Hippo pathway, including a critical role for Spectrin in coupling cortical tension, cell shape and Hippo signaling in retinal morphogenesis and the discovery of biomolecular condensates as a unified mechanism by which upstream regulators of the Hippo pathway integrate diverse physiological inputs into Hippo signaling. Our research also shed light on Hippo pathway evolution by uncovering a critical role for Hippo signaling in a unicellular relative of metazoans. Meanwhile, we continued to extend our Hippo pathway discoveries from Drosophila to mammalian biology. Highlights include our elucidation of default repression as well as polyamine biosynthesis and DNA demethylation as key transcriptional output of mammalian Hippo signaling and aberrant Hippo signaling as the pathological basis for epithelioid hemangioendothelioma (EHE). In the next grant period, we will further elucidate the molecular underpinnings of the Hippo pathway through the following specific aims. First, we will investigate the function and regulation of Slmap condensates in mechano- regulation of Hippo signaling. This aim will not only expand our understanding of Hippo pathway regulation by mechanical forces, but also define endoplasmic reticulum as a novel subcellular hub for mechano-transduction. Second, we will dissect the molecular and cellular mechanisms by which phosphatidylinositol-4-phosphate (PI4P) on plasma membrane integrates upstream inputs of Hippo signaling to regulate Merlin function. This aim will shed light on the control of plasma membrane PI4P level and distribution in developing tissues and define how diverse signals converge on PI4P to regulate Merlin function. Lastly, we will characterize novel regulators of the Hippo pathway identified from a sensitized genetic screen. This unbiased genetic approach will shed light on previously unforeseen regulators/mechanisms underlying Hippo pathway regulation. Besides revealing fundamental mechanisms of eye development, the proposed studies will have general implications for the development of other tissues.