Article abstract
Nature Genetics 40, 403 - 410 (2008)
Published online: 9 March 2008 | doi:10.1038/ng.105
THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia
Pamela V Tran1, Courtney J Haycraft2,6, Tatiana Y Besschetnova3,6, Annick Turbe-Doan1, Rolf W Stottmann1, Bruce J Herron1,5, Allyson L Chesebro1, Haiyan Qiu1, Paul J Scherz4, Jagesh V Shah3, Bradley K Yoder2 & David R Beier1
Abstract
Characterization of previously described intraflagellar transport (IFT) mouse mutants has led to the proposition that normal primary cilia are required for mammalian cells to respond to the sonic hedgehog (SHH) signal. Here we describe an N-ethyl-N-nitrosourea–induced mutant mouse, alien (aln), which has abnormal primary cilia and shows overactivation of the SHH pathway. The aln locus encodes a novel protein, THM1 (tetratricopeptide repeat–containing hedgehog modulator-1), which localizes to cilia. aln-mutant cilia have bulb-like structures at their tips in which IFT proteins (such as IFT88) are sequestered, characteristic of Chlamydomonas reinhardtii and Caenorhabditis elegans retrograde IFT mutants. RNA-interference knockdown of Ttc21b (which we call Thm1 and which encodes THM1) in mouse inner medullary collecting duct cells expressing an IFT88–enhanced yellow fluorescent protein fusion recapitulated the aln-mutant cilial phenotype, and live imaging of these cells revealed impaired retrograde IFT. In contrast to previously described IFT mutants, Smoothened and full-length glioblastoma (GLI) proteins localize to aln-mutant cilia. We hypothesize that the aln retrograde IFT defect causes sequestration of IFT proteins in aln-mutant cilia and leads to the overactivated SHH signaling phenotype. Specifically, the aln mutation uncouples the roles of anterograde and retrograde transport in SHH signaling, suggesting that anterograde IFT is required for GLI activation and that retrograde IFT modulates this event.
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, New Research Building, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Department of Cell Biology, University of Alabama, McCallum Building, 1918 University Boulevard, Birmingham, Alabama 35294, USA.
- Renal Division, Brigham and Women's Hospital, Harvard Institutes of Medicine, 4 Blackfan Circle, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Department of Genetics, Harvard Medical School, New Research Building, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Present address: Wadsworth Center, New York State Department of Health, Albany, New York, 12201, USA.
- These authors contributed equally to this work.
Correspondence to: David R Beier1 e-mail: beier@receptor.med.harvard.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Hedgehogs on the road to polarityNature Genetics News and Views (01 Mar 2006)
Hoxgenes, Arms and the ManNature Genetics News and Views (01 Feb 1997)
See all 5 matches for News And ViewsRESEARCH
Hedgehog signaling and primary cilia are required for the formation of adult neural stem cellsNature Neuroscience Article (01 Mar 2008)
Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specificationNature Genetics Letter (01 Jan 2006)
See all 33 matches for Research