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.
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.
|Zhang, Yifei; Wang, Xing; Matakatsu, Hitoshi et al. (2016) The novel SH3 domain protein Dlish/CG10933 mediates fat signaling in Drosophila by binding and regulating Dachs. Elife 5:|
|Schleede, Justin; Blair, Seth S (2015) The Gyc76C Receptor Guanylyl Cyclase and the Foraging cGMP-Dependent Kinase Regulate Extracellular Matrix Organization and BMP Signaling in the Developing Wing of Drosophila melanogaster. PLoS Genet 11:e1005576|
|Blair, Seth S (2014) Planar cell polarity: the importance of getting it backwards. Curr Biol 24:R835-8|
|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|
|Avanesov, Andrei; Honeyager, Shawn M; Malicki, Jarema et al. (2012) The role of glypicans in Wnt inhibitory factor-1 activity and the structural basis of Wif1's effects on Wnt and Hedgehog signaling. PLoS Genet 8:e1002503|
|Matakatsu, Hitoshi; Blair, Seth S (2012) Separating planar cell polarity and Hippo pathway activities of the protocadherins Fat and Dachsous. Development 139:1498-508|
|Chen, Jun; Honeyager, Shawn M; Schleede, Justin et al. (2012) Crossveinless d is a vitellogenin-like lipoprotein that binds BMPs and HSPGs, and is required for normal BMP signaling in the Drosophila wing. Development 139:2170-6|
|Blair, Seth S (2012) Cell polarity: overdosing on PCPs. Curr Biol 22:R567-9|
|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|
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