This proposal outlines a series of experiments designed to test and refine our understanding of the mechanisms by which the developing tissues precisely patterned. Such precision is essential to the normal human development, and analyzing the means by which such patterning arises is essential to both our understanding of normal fetal development, and for developing therapies for the recovery from disease and injury. The ability of researchers to experimentally analyze development in vertebrates is limited, however, by the complexity of the vertebrate genome and fetus. This proposal therefore outlines an ongoing seriesof experiments that analyze these problems in the developing appendages of the fruitly, Drosophila melanogaster. In the fruitfly wing, specific tissues arise in an extremely stereotyped fashion from a single layer of epithelial cells. Not only is this system simple, but the genetic and molecular tools available for work on Drosophila are unmatched by any other animal system. We will use a combination of genetic, histochemical and molecular techniques to analyze the developmental bases of the stereotyped neuronal development found in Drosophila. Our analyses include testing the roles of a number of known genes and signaling pathways, and searching for novel genes critical to the patterning process.
Our first aim i s to analyze the role of the secreted protein Shifted, a homolog of human Wnt Inhibitory Factor-1, and how it intercts with Hedgehog signaling during the induction of cells along compartment boundaries.
Our second aim i s examine a novel signaling mechanism by which two unusual protocadherins, Fat and Dachsous, regulate the growth and proximal-distal patterning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028202-19
Application #
7795696
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Riddle, Robert D
Project Start
1990-08-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
19
Fiscal Year
2010
Total Cost
$250,413
Indirect Cost
Name
University of Wisconsin Madison
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Matakatsu, Hitoshi; Blair, Seth S; Fehon, Richard G (2017) The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat. J Cell Biol 216:265-277
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-R838
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

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