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Growth regulation by the Fat signaling pathway

Kenneth D Irvine

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National Institutes of Health (NIH)
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 investigates 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 importantfor 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.

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