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THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia.
- Source :
-
Nature genetics [Nat Genet] 2008 Apr; Vol. 40 (4), pp. 403-410. Date of Electronic Publication: 2008 Mar 09. - Publication Year :
- 2008
-
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.
- Subjects :
- Alkylating Agents toxicity
Amino Acid Sequence
Animals
Biological Transport
Blotting, Western
Cells, Cultured
Cloning, Molecular
Ethylnitrosourea toxicity
Female
Fibroblasts metabolism
Genes, Recessive
In Situ Hybridization
Luminescent Proteins genetics
Luminescent Proteins metabolism
Male
Mice
Mice, Knockout
Molecular Sequence Data
Mutagenesis
Oncogene Proteins genetics
Oncogene Proteins metabolism
Sequence Homology, Amino Acid
Spinal Cord metabolism
Trans-Activators genetics
Trans-Activators metabolism
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Zinc Finger Protein GLI1
Adaptor Proteins, Signal Transducing physiology
Cilia metabolism
Hedgehog Proteins metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 40
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 18327258
- Full Text :
- https://doi.org/10.1038/ng.105