The long-term goal of this research is to understand the mechanisms of long-distance cell signaling that are important to development and to disease. We address these important issues with a model system, applying its powerful genetic and molecular techniques to identify and analyze key genes and processes. Our work has shown that in Drosophila, the hedgehog (hh) gene plays a central role setting up and regulating both the segments in the embryo and the compartment borders and signaling centers in the wing disc. Our recent work has focused on the activities of its receptor, Patched (Ptc) and on the transcription factor that mediates Hh signal transduction, Cubitus interruptus (Ci). The human orthologs of both Ptc and Ci have been implicated in a number of human diseases, including cancer.
Specific aims are proposed in this application to: (1) complete a forward genetic screen to identify additional components of the Hh signal transduction pathway; (2) identify novel targets of Hh signal transduction using complementary molecular approaches; (3) characterize the structure and regulation of the Patched receptor; (4) analyze the conversion of Ci to its repressor and activator forms; and (5) describe the mechanism by which Hh moves from its sites of synthesis to engage its receptor in neighboring or a distant cells. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077407-02
Application #
7222793
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Haynes, Susan R
Project Start
2006-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$277,488
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Casso, David J; Liu, Songmei; Biehs, Brian et al. (2012) Expression and characterization of Drosophila signal peptide peptidase-like (sppL), a gene that encodes an intramembrane protease. PLoS One 7:e33827
Kornberg, Thomas B (2011) Barcoding Hedgehog for intracellular transport. Sci Signal 4:pe44
Casso, David J; Biehs, Brian; Kornberg, Thomas B (2011) A novel interaction between hedgehog and Notch promotes proliferation at the anterior-posterior organizer of the Drosophila wing. Genetics 187:485-99
Kechris, Katerina J; Biehs, Brian; Kornberg, Thomas B (2010) Generalizing moving averages for tiling arrays using combined p-value statistics. Stat Appl Genet Mol Biol 9:Article29
Biehs, Brian; Kechris, Katerina; Liu, Songmei et al. (2010) Hedgehog targets in the Drosophila embryo and the mechanisms that generate tissue-specific outputs of Hedgehog signaling. Development 137:3887-98
Kawamura, Shiho; Hervold, Kieran; Ramirez-Weber, Felipe-Andres et al. (2008) Two patched protein subtypes and a conserved domain of group I proteins that regulates turnover. J Biol Chem 283:30964-9
Kornberg, Thomas B; Guha, Arjun (2007) Understanding morphogen gradients: a problem of dispersion and containment. Curr Opin Genet Dev 17:264-71