Our objectives are to study the mechanisms of Hedgehog signal transduction in Drosophila and how Hedgehog signaling affects cell proliferation in the Drosophila ovary. Hedgehog family proteins are secreted molecules that instruct cell fate during development and can regulate cell proliferation even in adult organisms. These activities of Hedgehog (Hh) molecules are seen in many organisms from Drosophila, where Hh was first identified, to vertebrates including fish, frogs, mice and humans. In humans various defects in the Hh signaling pathway cause developmental abnormalities principally involving limbs, brain and facial structures (Holoprosencephaly, Grolin's syndrome, Greig's cephalopolysyndactyl, Pallister-Hall syndrome). In addition, a few specific cancers are associated with aberrantly activated Hh signaling pathway. Indeed, basal cell carcinoma, which is very widespread, is thought to be initiated exclusively by aberrant Hh signaling. The study of Hh signaling in Drosophila has brought many insights into the transduction process by which cells respond to a Hh signal and has also provided insight into how cells behaviors are altered by Hh signaling. The relative facility and sophistication of Genetic and Developmental analyses that are possible in Drosophila ensure that the pioneering role of such studies will continue. Subsequent studies have shown that most of the components and mechanisms of Hh signal transduction elucidated in Drosophila can also be demonstrated in vertebrate model organisms. In particular the role of Protein Kinase A (PKA) in silencing Hh signal transduction in the absence of a Hh signal is apparent in Drosophila and vertebrates. Our study of this role of PKA recently implicated additional protein kinases as regulators of Hh signaling. In this proposal we will define the role of these protein kinases and PKA in Hh signaling. We also found that Hh regulates proliferation in the Drosophila ovary by acting specifically on stem cells. We will define which other signaling pathways regulate these stem cells and how Hh alters their behavior. These studies are likely to be directly relevant to the behavior of human stem cells that give rise to hair follicles and epidermis and should help us to understand how basal cell carcinomas can originate from those stem cells or their derivatives.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041815-17
Application #
6855782
Study Section
Genetics Study Section (GEN)
Program Officer
Haynes, Susan R
Project Start
1989-04-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
17
Fiscal Year
2005
Total Cost
$367,558
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Garcia-Garcia, Elisa; Little, Jamie C; Kalderon, Daniel (2017) The Exon Junction Complex and Srp54 Contribute to Hedgehog Signaling via ci RNA Splicing in Drosophila melanogaster. Genetics 206:2053-2068
Zadorozny, Eva V; Little, Jamie C; Kalderon, Daniel (2015) Contributions of Costal 2-Fused interactions to Hedgehog signaling in Drosophila. Development 142:931-42
Marks, Steven A; Kalderon, Daniel (2011) Regulation of mammalian Gli proteins by Costal 2 and PKA in Drosophila reveals Hedgehog pathway conservation. Development 138:2533-42
Zhou, Qianhe; Kalderon, Daniel (2011) Hedgehog activates fused through phosphorylation to elicit a full spectrum of pathway responses. Dev Cell 20:802-14
Gleason, Julie E; Eisenmann, David M (2010) Wnt signaling controls the stem cell-like asymmetric division of the epithelial seam cells during C. elegans larval development. Dev Biol 348:58-66
Zhou, Qianhe; Kalderon, Daniel (2010) Costal 2 interactions with Cubitus interruptus (Ci) underlying Hedgehog-regulated Ci processing. Dev Biol 348:47-57
Vied, Cynthia; Kalderon, Daniel (2009) Hedgehog-stimulated stem cells depend on non-canonical activity of the Notch co-activator Mastermind. Development 136:2177-86
Smelkinson, Margery G; Zhou, Qianhe; Kalderon, Daniel (2007) Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation. Dev Cell 13:481-95
Smelkinson, Margery G; Kalderon, Daniel (2006) Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component Slimb. Curr Biol 16:110-6
Zhou, Qianhe; Apionishev, Sergey; Kalderon, Daniel (2006) The contributions of protein kinase A and smoothened phosphorylation to hedgehog signal transduction in Drosophila melanogaster. Genetics 173:2049-62

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