The goal of this proposal is to determine how growth and polarity are regulated in developing tissues to form organs of appropriate size and shape. We will investigate two processes that play fundamental yet incompletely understood roles in controlling organ size and shape: Ds-Fat signaling and cytoskeletal tension. A remarkable feature of Ds-Fat signaling is that it can be regulated by the vector and slope of Dachsous (Ds) and Four-jointed (Fj) gradients to influence distinct downstream processes that control planar cell polarity (PCP) and, through regulation of Hippo signaling, growth. These gradients polarize Fat activity within cells, as can be visualized by the polarization of the Fat signaling component Dachs. Characterization of this pathway will provide novel insights into the control of cell behavior, and how patterning and growth can be linked during development. It has also been proposed that mechanical forces could play roles in modulating organ size and shape, but the mechanisms by which this occurs are not well understood. Recent studies however, including our characterization of the regulation and role of the Jub protein, have implicated the Hippo signaling pathway in regulation of growth by mechanical forces. The studies proposed here will enhance molecular understanding of how patterning, e.g. as provided by morphogen gradients, directs organogenesis, how mechanical forces within and between cells modulate organogenesis, and how these biochemical and biomechanical processes are integrated.
The first aim proposes studies to define molecular mechanisms that control the accumulation and polarity of the key Fat signaling component Dachs.
The second aim will focus on defining mechanisms by which Dachs and other factors influence planar cell polarity, including both tension-dependent and tension-independent processes.
The third aim i nvestigates molecular mechanisms that regulate the key Hippo pathway kinase Warts to control growth, and interrelationships among growth-regulatory processes that affect Warts. The proposed studies will provide a deeper understanding of mechanisms that control tissue polarity, and that control growth through Hippo signaling. Organ shape is crucial for normal organ function, and specific requirements for Ds-Fat signaling in humans have been revealed by its association with Van Maldergem syndrome. 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 Hippo signaling, including liver, kidney, skin, brain, intestine, lung, ovary, breast, and prostate Understanding the regulation of Hippo signaling is thus relevant to a range of human health issues, including birth defects, cancer, and regenerative medicine.
This proposal investigates mechanisms that control organ and tissue growth. We focus on conserved intercellular signaling pathways, Dachsous-Fat and Hippo; understanding these pathways will facilitate diagnosis and treatment of diseases. 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. Additionally, the inability to limit growth in mature organisms results in cancer, and inactivation of the Hippo pathway in humans is linked to many types of cancer.
| Misra, Jyoti R; Irvine, Kenneth D (2018) The Hippo Signaling Network and Its Biological Functions. Annu Rev Genet 52:65-87 |
| Pan, Yuanwang; Alégot, 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 |
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