Intraflagellar transport is deeply integrated in hedgehog signaling

Mol Biol Cell. 2018 May 15;29(10):1178-1189. doi: 10.1091/mbc.E17-10-0600. Epub 2018 Mar 22.

Abstract

The vertebrate hedgehog pathway is organized in primary cilia, and hedgehog components relocate into or out of cilia during signaling. Defects in intraflagellar transport (IFT) typically disrupt ciliary assembly and attenuate hedgehog signaling. Determining whether IFT drives the movement of hedgehog components is difficult due to the requirement of IFT for building cilia. Unlike most IFT proteins, IFT27 is dispensable for cilia formation but affects hedgehog signaling similarly to other IFTs, allowing us to examine its role in the dynamics of signaling. Activating signaling at points along the pathway in Ift27 mutant cells showed that IFT is extensively involved in the pathway. Similar analysis of Bbs mutant cells showed that BBS proteins participate at many levels of signaling but are not needed to concentrate Gli transcription factors at the ciliary tip. Our analysis showed that smoothened delivery to cilia does not require IFT27, but the role of other IFTs is not known. Using a rapamycin-induced dimerization system to sequester IFT-B proteins at the mitochondria in cells with fully formed cilia did not affect the delivery of Smo to cilia, suggesting that this membrane protein may not require IFT-B for delivery.

Publication types

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

MeSH terms

  • Animals
  • Biological Transport
  • Cilia / metabolism
  • Flagella / metabolism*
  • Hedgehog Proteins / metabolism*
  • Humans
  • Mice
  • Mitochondria / metabolism
  • Mutation / genetics
  • Signal Transduction*
  • Smoothened Receptor / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • Hedgehog Proteins
  • Smo protein, mouse
  • Smoothened Receptor
  • intraflagellar transport 27 protein, mouse
  • rab GTP-Binding Proteins