GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:18327258

From GONUTS
Jump to: navigation, search
Citation

Tran, PV, Haycraft, CJ, Besschetnova, TY, Turbe-Doan, A, Stottmann, RW, Herron, BJ, Chesebro, AL, Qiu, H, Scherz, PJ, Shah, JV, Yoder, BK and Beier, DR (2008) THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat. Genet. 40:403-10

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.

Links

PubMed Online version:10.1038/ng.105

Keywords

Adaptor Proteins, Signal Transducing/physiology; Alkylating Agents/toxicity; Amino Acid Sequence; Animals; Biological Transport; Blotting, Western; Cells, Cultured; Cilia/metabolism; Cloning, Molecular; Ethylnitrosourea/toxicity; Female; Fibroblasts/metabolism; Genes, Recessive; Hedgehog Proteins/metabolism; 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; Signal Transduction; Spinal Cord/metabolism; Trans-Activators/genetics; Trans-Activators/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TT21B

involved_in

GO:0007224: smoothened signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2152544

P

Seeded From UniProt

complete

MOUSE:TT21B

involved_in

GO:0035721: intraciliary retrograde transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.