Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Patched1 Regulates Hedgehog Signaling at the Primary Cilium
Rajat Rohatgi,1,2*Ljiljana Milenkovic,1*Matthew P. Scott1
Primary cilia are essential for transduction of the Hedgehog(Hh) signal in mammals. We investigated the role of primarycilia in regulation of Patched1 (Ptc1), the receptor for SonicHedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened(Smo) by preventing its accumulation within cilia. When Shhbound to Ptc1, Ptc1 left the cilia, leading to accumulationof Smo and activation of signaling. Thus, primary cilia senseShh and transduce signals that play critical roles in development,carcinogenesis, and stem cell function.
1 Departments of Developmental Biology, Genetics, and Bioengineering and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. 2 Department of Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: mscott{at}stanford.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
PERSPECTIVES
Søren Tvorup Christensen and Carolyn Marie Ott (20 July 2007) Science317 (5836), 330.
[DOI: 10.1126/science.1146180] |Summary »|Full Text »|PDF »
In Science Signaling
EDITORS' CHOICE
L. Bryan Ray (24 July 2007) Sci. STKE2007 (396), tw261.
[DOI: 10.1126/stke.3962007tw261] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway.
V. L. Patterson, C. Damrau, A. Paudyal, B. Reeve, D. T. Grimes, M. E. Stewart, D. J. Williams, P. Siggers, A. Greenfield, and J. N. Murdoch (2009)
Hum. Mol. Genet.
18, 1719-1739
|Abstract »|Full Text »|PDF »
Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling.
R. X. Norman, H. W. Ko, V. Huang, C. M. Eun, L. L. Abler, Z. Zhang, X. Sun, and J. T. Eggenschwiler (2009)
Hum. Mol. Genet.
18, 1740-1754
|Abstract »|Full Text »|PDF »
Primary cilia regulate Shh activity in the control of molar tooth number.
A. Ohazama, C. J. Haycraft, M. Seppala, J. Blackburn, S. Ghafoor, M. Cobourne, D. C. Martinelli, C.-M. Fan, R. Peterkova, H. Lesot, et al. (2009)
Development
136, 897-903
|Abstract »|Full Text »|PDF »
Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process.
R. Rohatgi, L. Milenkovic, R. B. Corcoran, and M. P. Scott (2009)
PNAS
106, 3196-3201
|Abstract »|Full Text »|PDF »
Activation of Hedgehog Signaling Inhibits Osteoblast Differentiation of Human Mesenchymal Stem Cells.
M. Plaisant, C. Fontaine, W. Cousin, N. Rochet, C. Dani, and P. Peraldi (2009)
Stem Cells
27, 703-713
|Abstract »|Full Text »|PDF »
Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation.
Y. Wang, Z. Zhou, C. T. Walsh, and A. P. McMahon (2009)
PNAS
106, 2623-2628
|Abstract »|Full Text »|PDF »
The Talpid3 gene (KIAA0586) encodes a centrosomal protein that is essential for primary cilia formation.
Y. Yin, F. Bangs, I. R. Paton, A. Prescott, J. James, M. G. Davey, P. Whitley, G. Genikhovich, U. Technau, D. W. Burt, et al. (2009)
Development
136, 655-664
|Abstract »|Full Text »|PDF »
Characterization of PKD Protein-Positive Exosome-Like Vesicles.
M. C. Hogan, L. Manganelli, J. R. Woollard, A. I. Masyuk, T. V. Masyuk, R. Tammachote, B. Q. Huang, A. A. Leontovich, T. G. Beito, B. J. Madden, et al. (2009)
J. Am. Soc. Nephrol.
20, 278-288
|Abstract »|Full Text »|PDF »
Pancreatic Cancer and Precursor Pancreatic Intraepithelial Neoplasia Lesions Are Devoid of Primary Cilia.
E. S. Seeley, C. Carriere, T. Goetze, D. S. Longnecker, and M. Korc (2009)
Cancer Res.
69, 422-430
|Abstract »|Full Text »|PDF »
C2cd3 is required for cilia formation and Hedgehog signaling in mouse.
A. N. Hoover, A. Wynkoop, H. Zeng, J. Jia, L. A. Niswander, and A. Liu (2008)
Development
135, 4049-4058
|Abstract »|Full Text »|PDF »
Smoothened Signaling in Vertebrates Is Facilitated by a G Protein-coupled Receptor Kinase.
M. Philipp, G. B. Fralish, A. R. Meloni, W. Chen, A. W. MacInnes, L. S. Barak, and M. G. Caron (2008)
Mol. Biol. Cell
19, 5478-5489
|Abstract »|Full Text »|PDF »
Kinome siRNA Screen Identifies Regulators of Ciliogenesis and Hedgehog Signal Transduction.
M. Evangelista, T. Y. Lim, J. Lee, L. Parker, A. Ashique, A. S. Peterson, W. Ye, D. P. Davis, and F. J. de Sauvage (2008)
Science Signaling
1, ra7
|Abstract »|Full Text »|PDF »
Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network.
E. Dessaud, A. P. McMahon, and J. Briscoe (2008)
Development
135, 2489-2503
|Abstract »|Full Text »|PDF »
A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells.
J. N. Passman, X. R. Dong, S.-P. Wu, C. T. Maguire, K. A. Hogan, V. L. Bautch, and M. W. Majesky (2008)
PNAS
105, 9349-9354
|Abstract »|Full Text »|PDF »
Sonic hedgehog is associated with H+-K+-ATPase-containing membranes in gastric parietal cells and secreted with histamine stimulation.
Y. Zavros, M. A. Orr, C. Xiao, and D. H. Malinowska (2008)
Am J Physiol Gastrointest Liver Physiol
295, G99-G111
|Abstract »|Full Text »|PDF »
{beta}-Arrestin-Mediated Localization of Smoothened to the Primary Cilium.
J. J. Kovacs, E. J. Whalen, R. Liu, K. Xiao, J. Kim, M. Chen, J. Wang, W. Chen, and R. J. Lefkowitz (2008)
Science
320, 1777-1781
|Abstract »|Full Text »|PDF »
Polycystin-1 Regulates Skeletogenesis through Stimulation of the Osteoblast-specific Transcription Factor RUNX2-II.
Z. Xiao, S. Zhang, B. S. Magenheimer, J. Luo, and L. D. Quarles (2008)
J. Biol. Chem.
283, 12624-12634
|Abstract »|Full Text »|PDF »
The Adventures of Sonic Hedgehog in Development and Repair. IV. Sonic hedgehog processing, secretion, and function in the stomach.
Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning.
C. E. Chamberlain, J. Jeong, C. Guo, B. L. Allen, and A. P. McMahon (2008)
Development
135, 1097-1106
|Abstract »|Full Text »|PDF »
Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery.
E. N. Kiprilov, A. Awan, R. Desprat, M. Velho, C. A. Clement, A. G. Byskov, C. Y. Andersen, P. Satir, E. E. Bouhassira, S. T. Christensen, et al. (2008)
J. Cell Biol.
180, 897-904
|Abstract »|Full Text »|PDF »
Timing Neurogenesis and Differentiation: Insights from Quantitative Clonal Analyses of Cerebellar Granule Cells.