The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking

J Cell Biol. 2012 Jun 11;197(6):789-800. doi: 10.1083/jcb.201110049.

Abstract

Two intraflagellar transport (IFT) complexes, IFT-A and IFT-B, build and maintain primary cilia and are required for activity of the Sonic hedgehog (Shh) pathway. A weak allele of the IFT-A gene, Ift144, caused subtle defects in cilia structure and ectopic activation of the Shh pathway. In contrast, strong loss of IFT-A, caused by either absence of Ift144 or mutations in two IFT-A genes, blocked normal ciliogenesis and decreased Shh signaling. In strong IFT-A mutants, the Shh pathway proteins Gli2, Sufu, and Kif7 localized correctly to cilia tips, suggesting that these pathway components were trafficked by IFT-B. In contrast, the membrane proteins Arl13b, ACIII, and Smo failed to localize to primary cilia in the absence of IFT-A. We propose that the increased Shh activity seen in partial loss-of-function IFT-A mutants may be a result of decreased ciliary ACIII and that the loss of Shh activity in the absence of IFT-A is a result of severe disruptions of cilia structure and membrane protein trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cilia / metabolism
  • Cilia / ultrastructure*
  • Cytoskeletal Proteins
  • Flagella / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kinesins / genetics
  • Kinesins / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron
  • Proteins / genetics
  • Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction*
  • Zinc Finger Protein Gli2

Substances

  • Cytoskeletal Proteins
  • Gli2 protein, mouse
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Proteins
  • Repressor Proteins
  • Sufu protein, mouse
  • Wdr19 protein, mouse
  • Zinc Finger Protein Gli2
  • Kif7 protein, mouse
  • Kinesins