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. Much of our recent efforts have focused on discovering the missing components of the Hippo pathway, with the ultimate goal of defining a complete Hippo signaling network that relays information from the extracellular milieu to nuclear gene transcription. We have made significant progress in the last grant period, including 1) the discovery of Crumbs as an apically localized transmembrane protein that regulates Hippo signaling by directly binding and localizing the tumor suppressor Expanded to apical membranes;2) discovery of a functionally conserved Hippo pathway in organisms representing unicellular relatives of Metazoa;3) discovery of verteporfin as the first small molecule inhibitor for Yki and its mammalian homologue YAP;4) discovery of default repression as a fundamental mechanism underlying Hippo-mediated growth regulation by demonstrating that Sd functions by default as a transcriptional repressor;5) elucidating the molecular mechanism by which Merlin regulates Hippo signaling by demonstrating a requirement for Merlin in direct binding and recruitment of the effector kinase Wts to the plasma membrane. In the coming project period, we will further elucidate the composition and regulation of the Hippo pathway through the following aims. First, we have identified, through biochemical screens, another protein kinase that can phosphorylate and activate Wts in a similar manner as Hpo. Our goal in this aim is to characterize the role of this Hpo-like kinase in growth control and Hippo signaling in vivo. Second, we have identified, through phenotype-based screens, a novel tumor suppressor that regulates Hippo signaling in a non-cell autonomous manner as well as a tumor suppressor complex that regulates Hippo signaling in a cell-autonomous manner. Our goal in this aim is to understand the molecular mechanisms by which these novel tumor suppressors regulate the Hippo pathway. Lastly, we have designed a sensitized genetic screen to identify additional components of the Hippo pathway. Our goal in this aim is to complete the genetic screen and to molecularly characterize candidate genes identified from the screen. Besides revealing fundamental mechanisms of eye development, the proposed studies will have general implications for the development of other tissues.

Public Health Relevance

The proposed studies will not only elucidate the fundamental mechanisms that regulate retina cell number, but also provide general insights into how cell number is determined in other organs during animal development and how aberrant regulation of this process could lead to tissue atrophy or hyperplasia. Such insights may facilitate the therapeutic interventions of relevant human diseases, including diseases of the retina.

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Greenwell, Thomas
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Johns Hopkins University
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Qing, Yun; Yin, Feng; Wang, Wei et al. (2014) The Hippo effector Yorkie activates transcription by interacting with a histone methyltransferase complex through Ncoa6. Elife 3:
Yin, Feng; Yu, Jianzhong; Zheng, Yonggang et al. (2013) Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 154:1342-55
Koontz, Laura M; Liu-Chittenden, Yi; Yin, Feng et al. (2013) The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev Cell 25:388-401
Yu, Jianzhong; Zheng, Yonggang; Dong, Jixin et al. (2010) Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18:288-99
Pan, Duojia (2010) The hippo signaling pathway in development and cancer. Dev Cell 19:491-505
Ling, Chen; Zheng, Yonggang; Yin, Feng et al. (2010) The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A 107:10532-7
Tian, Wei; Yu, Jianzhong; Tomchick, Diana R et al. (2010) Structural and functional analysis of the YAP-binding domain of human TEAD2. Proc Natl Acad Sci U S A 107:7293-8
Alarcon, Claudio; Zaromytidou, Alexia-Ileana; Xi, Qiaoran et al. (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139:757-69
Wu, Shian; Liu, Yi; Zheng, Yonggang et al. (2008) The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell 14:388-98
Dong, Jixin; Feldmann, Georg; Huang, Jianbin et al. (2007) Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130:1120-33

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