PUBLICATION
Neuropilins are positive regulators of Hedgehog signal transduction
- Authors
- Hillman, R.T., Feng, B.Y., Ni, J., Woo, W.M., Milenkovic, L., Hayden Gephart, M.G., Teruel, M.N., Oro, A.E., Chen, J.K., and Scott, M.P.
- ID
- ZDB-PUB-111117-15
- Date
- 2011
- Source
- Genes & Development 25(22): 2333-46 (Journal)
- Registered Authors
- Chen, James K., Feng, Brian
- Keywords
- neuropilins, Hedgehog pathway, development, zebrafish, primary cilium
- MeSH Terms
-
- Animals
- Feedback, Physiological
- Gene Expression Regulation, Developmental
- Hedgehog Proteins/metabolism*
- Mice
- Neuropilin-1/genetics
- Neuropilin-1/metabolism
- Neuropilin-2/genetics
- Neuropilin-2/metabolism
- Neuropilins/metabolism*
- RNA Interference
- Receptors, G-Protein-Coupled/metabolism
- Repressor Proteins/metabolism
- Signal Transduction*
- PubMed
- 22051878 Full text @ Genes & Dev.
Citation
Hillman, R.T., Feng, B.Y., Ni, J., Woo, W.M., Milenkovic, L., Hayden Gephart, M.G., Teruel, M.N., Oro, A.E., Chen, J.K., and Scott, M.P. (2011) Neuropilins are positive regulators of Hedgehog signal transduction. Genes & Development. 25(22):2333-46.
Abstract
The Hedgehog (Hh) pathway is essential for vertebrate embryogenesis, and excessive Hh target gene activation can cause cancer
in humans. Here we show that Neuropilin 1 (Nrp1) and Nrp2, transmembrane proteins with roles in axon guidance and vascular
endothelial growth factor (VEGF) signaling, are important positive regulators of Hh signal transduction. Nrps are expressed
at times and locations of active Hh signal transduction during mouse development. Using cell lines lacking key Hh pathway
components, we show that Nrps mediate Hh transduction between activated Smoothened (Smo) protein and the negative regulator
Suppressor of Fused (SuFu). Nrp1 transcription is induced by Hh signaling, and Nrp1 overexpression increases maximal Hh target gene activation, indicating the existence of a positive feedback circuit. The
regulation of Hh signal transduction by Nrps is conserved between mammals and bony fish, as we show that morpholinos targeting
the Nrp zebrafish ortholog nrp1a produce a specific and highly penetrant Hh pathway loss-of-function phenotype. These findings enhance our knowledge of Hh
pathway regulation and provide evidence for a conserved nexus between Nrps and this important developmental signaling system.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping