The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment

Nat Cell Biol. 2014 Jul;16(7):663-72. doi: 10.1038/ncb2988. Epub 2014 Jun 22.

Abstract

Mammalian Hedgehog (Hh) signal transduction requires a primary cilium, a microtubule-based organelle, and the Gli-Sufu complexes that mediate Hh signalling, which are enriched at cilia tips. Kif7, a kinesin-4 family protein, is a conserved regulator of the Hh signalling pathway and a human ciliopathy protein. Here we show that Kif7 localizes to the cilium tip, the site of microtubule plus ends, where it limits cilium length and controls cilium structure. Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. Kif7 is not required for normal intraflagellar transport or for trafficking of Hh pathway proteins into cilia. Instead, a central function of Kif7 in the mammalian Hh pathway is to control cilium architecture and to create a single cilium tip compartment, where Gli-Sufu activity can be correctly regulated.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axoneme / genetics
  • Axoneme / metabolism
  • Cell Line
  • Cells, Cultured
  • Cilia / chemistry
  • Cilia / metabolism*
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kinesin / genetics
  • Kinesin / metabolism*
  • Mice
  • Microtubules / metabolism
  • Mutation
  • NIH 3T3 Cells
  • Protein Binding
  • Protein Transport
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction*

Substances

  • Hedgehog Proteins
  • Recombinant Proteins
  • Kif7 protein, mouse
  • Kinesin