The goal of this proposal is to provide a molecular understanding of how tissue growth and polarity are linked to patterning by the Fat-Hippo signaling pathway. These studies will elucidate the workings of this novel intercellular signaling pathway, which regulates growth during both normal development and in pathological conditions. The Drosophila fat gene encodes a large cadherin protein that acts as a receptor for Fat signaling. Two genes have been identified as regulators of Fat: dachsous (ds), which encodes a large cadherin that acts as a ligand for Fat, and four-jointed (fj), which encodes a Golgi-localized kinase that phosphorylates cadherin domains of Fat and Ds to modulate binding between them. One remarkable feature of Fat signaling is that it can be regulated by a unique mechanism, which involves responding to the vector and slope of Ds and Fj gradients to influence distinct downstream processes that affect planar cell polarity (PCP) and growth. These gradients polarize Fat activity within cells, as visualized by the localization of the Fat signaling component Dachs. Characterization of this novel form of signaling pathway regulation will provide novel insights into the control of cell behavior, and how patterning and growth can be linked during development.
The first aim of the proposal is to explore the parameters of gradient sensing by the Fat pathway, using genetic and cell biological manipulations in the model system Drosophila melanogaster.
The second aim will characterize and define initial steps in Fat signaling, including the influence of Fat on the localization and activity of the myosin Dachs.
The third aim i nvestigates recently identified positive regulators of Fat-Hippo signlaing, and the transmission of Fat signaling to the kinase Warts. These studies will employ a combination of biochemical, cell biological, and genetic techniques in Drosophila. The proposed studies will provide a deeper understanding of the molecular basis for Fat-Hippo signaling, which is an important and conserved regulator of growth from Drosophila to humans. As inappropriate growth during development results in organs that are incorrectly sized or shaped, it can cause birth defects. Controlling organ growth is also important for understanding how stem cells can be used to repair or replace damaged organs, which is a goal of regenerative medicine. Additionally, the inability to limit growth in mature organisms results in cancer. Cancers in a wide variety of organs have been associated with inactivation of Fat- Hippo signaling, including liver, kidney, skin, brain, intestine, lung, ovary, breast, and prostate. Understanding the regulation of Fat-Hippo signaling is thus relevant to a range of human health issues, including birth defects, cancer, and regenerative medicine.

Public Health Relevance

This proposal investigates mechanisms that control organ and tissue growth during development. We focus on a conserved intercellular signaling pathway, known as Fat-Hippo signaling. Inappropriate growth during development results in organs that are incorrectly sized or shaped, causing birth defects. Controlling organ growth is also important for understanding how stem cells can be used to repair or replace damaged organs, which is a goal of regenerative medicine. Additionally, the inability to limit growth in mature organisms results in cancer, and mutations in many of the components of the Fat-Hippo pathway have been associated with cancer. Understanding these processes will facilitate diagnosis and treatment of diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM078620-08
Application #
8653964
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
None
Type
Organized Research Units
DUNS #
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Rauskolb, Cordelia; Sun, Shuguo; Sun, Gongping et al. (2014) Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell 158:143-56
Oh, Hyangyee; Slattery, Matthew; Ma, Lijia et al. (2014) Yorkie promotes transcription by recruiting a histone methyltransferase complex. Cell Rep 8:449-59
Pan, Guohui; Feng, Yongqiang; Ambegaonkar, Abhijit A et al. (2013) Signal transduction by the Fat cytoplasmic domain. Development 140:831-42
Reddy, B V V G; Irvine, Kenneth D (2013) Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev Cell 24:459-71
Oh, Hyangyee; Slattery, Matthew; Ma, Lijia et al. (2013) Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell Rep 3:309-18
Staley, Binnaz Kucuk; Irvine, Kenneth D (2012) Hippo signaling in Drosophila: recent advances and insights. Dev Dyn 241:3-15
Rauskolb, Cordelia; Pan, Guohui; Reddy, B V V G et al. (2011) Zyxin links fat signaling to the hippo pathway. PLoS Biol 9:e1000624
Oh, Hyangyee; Irvine, Kenneth D (2011) Cooperative regulation of growth by Yorkie and Mad through bantam. Dev Cell 20:109-22
Oh, Hyangyee; Irvine, Kenneth D (2010) Yorkie: the final destination of Hippo signaling. Trends Cell Biol 20:410-7
Simon, Michael A; Xu, Aiguo; Ishikawa, Hiroyuki O et al. (2010) Modulation of fat:dachsous binding by the cadherin domain kinase four-jointed. Curr Biol 20:811-7

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