This proposal outlines a series of experiments designed to test the regulation of an important intracellular pathway for controlling growth, cell death and patterning in developing organisms: that mediated by the Hippo and Warts protein kinases. This pathway plays a major role in controlling organ growth, and misregulation of the pathway is tumorigenic, but little is known about how it is controlled. We are concentrating on how this pathway is regulated by the large Drosophila protocadherins Fat and Dachsous. The extracellular domains of these two transmembrane proteins bind each other, and this suppresses growth by activating the Hippo pathway. However, the mechanisms connecting Fat and Dachsous to the Hippo pathway are poorly understood. First, we are dissecting the activities of the intracellular domains of Fat, and are using that to develop an in vitro RNAi screen for molecules required for Fat activity. Second, we are examining how boundaries and gradients of Fat and Dachsous expression, and the resultant polarization of Fat and Dachsous on cell surfaces, inhibits the Hippo pathway and triggers growth. Third, we are examining the role of a downstream negative regulator of Fat activity, the atypical myosin Dachs/Myosin29D, and its regulator Approximated. Finally, we are examining how the Hippo pathway combines with additional (especially spatial) information to regulate the expression of an important downstream target, the miRNA bantam.

Public Health Relevance

The experiments test and refine our knowledge about how developing organisms precisely control their growth and patterning. Such precision is essential to normal human development, and failure in such precision underlies many pathologies, including genetic defects and cancers. The pathway being studied is an important means for controlling growth that is shared by humans and other organisms;it can be profitably examined in Drosophila because of Drosophila's genetic and molecular advantages, and the rigor and speed with which such studies can be performed.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Development - 1 Study Section (DEV1)
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Riddle, Robert D
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Avanesov, Andrei; Blair, Seth S (2013) The Drosophila WIF1 homolog Shifted maintains glypican-independent Hedgehog signaling and interacts with the Hedgehog co-receptors Ihog and Boi. Development 140:107-16
Matakatsu, Hitoshi; Blair, Seth S (2012) Separating planar cell polarity and Hippo pathway activities of the protocadherins Fat and Dachsous. Development 139:1498-508
Sopko, Richelle; Silva, Elizabeth; Clayton, Lesley et al. (2009) Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown. Curr Biol 19:1112-7
Matakatsu, Hitoshi; Blair, Seth S (2008) The DHHC palmitoyltransferase approximated regulates Fat signaling and Dachs localization and activity. Curr Biol 18:1390-5
Serpe, Mihaela; Umulis, David; Ralston, Amy et al. (2008) The BMP-binding protein Crossveinless 2 is a short-range, concentration-dependent, biphasic modulator of BMP signaling in Drosophila. Dev Cell 14:940-53
Matakatsu, Hitoshi; Blair, Seth S (2006) Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133:2315-24
Ralston, Amy; Blair, Seth S (2005) Long-range Dpp signaling is regulated to restrict BMP signaling to a crossvein competent zone. Dev Biol 280:187-200
Serpe, Mihaela; Ralston, Amy; Blair, Seth S et al. (2005) Matching catalytic activity to developmental function: tolloid-related processes Sog in order to help specify the posterior crossvein in the Drosophila wing. Development 132:2645-56
Glise, Bruno; Miller, Catherine A; Crozatier, Michele et al. (2005) Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. Dev Cell 8:255-66
Conley, C A; Silburn, R; Singer, M A et al. (2000) Crossveinless 2 contains cysteine-rich domains and is required for high levels of BMP-like activity during the formation of the cross veins in Drosophila. Development 127:3947-59

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