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)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078620-07
Application #
8463558
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2007-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
7
Fiscal Year
2013
Total Cost
$254,309
Indirect Cost
$83,504
Name
Rutgers University
Department
Type
Organized Research Units
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Misra, Jyoti R; Irvine, Kenneth D (2018) The Hippo Signaling Network and Its Biological Functions. Annu Rev Genet 52:65-87
Pan, Yuanwang; Al├ęgot, Herve; Rauskolb, Cordelia et al. (2018) The dynamics of Hippo signaling during Drosophila wing development. Development 145:
Irvine, Kenneth D; Shraiman, Boris I (2017) Mechanical control of growth: ideas, facts and challenges. Development 144:4238-4248
Bilder, David; Irvine, Kenneth D (2017) Taking Stock of the Drosophila Research Ecosystem. Genetics 206:1227-1236
Pan, Yuanwang; Heemskerk, Idse; Ibar, Consuelo et al. (2016) Differential growth triggers mechanical feedback that elevates Hippo signaling. Proc Natl Acad Sci U S A 113:E6974-E6983
Misra, Jyoti R; Irvine, Kenneth D (2016) Vamana Couples Fat Signaling to the Hippo Pathway. Dev Cell 39:254-266
Sun, Shuguo; Irvine, Kenneth D (2016) Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network. Trends Cell Biol 26:694-704
Ambegaonkar, Abhijit A; Irvine, Kenneth D (2015) Coordination of planar cell polarity pathways through Spiny-legs. Elife 4:
Irvine, Kenneth D; Harvey, Kieran F (2015) Control of organ growth by patterning and hippo signaling in Drosophila. Cold Spring Harb Perspect Biol 7:
Rauskolb, Cordelia; Sun, Shuguo; Sun, Gongping et al. (2014) Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell 158:143-156

Showing the most recent 10 out of 27 publications