Hedgehog signaling regulates ciliary localization of mouse odorant receptors

Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9386-E9394. doi: 10.1073/pnas.1708321114. Epub 2017 Oct 16.

Abstract

The ciliary localization of odorant receptors (ORs) is evolutionary conserved and essential for olfactory transduction. However, how the transport of ORs is regulated in mammalian olfactory sensory neurons is poorly understood. Here we demonstrate that odorant responsiveness and OR transport is regulated by the Hedgehog pathway. OR transport is inhibited by conditional gene inactivation of the Hedgehog signal mediator Smoothened (Smo) as well as by systemic administration of the Smo inhibitor vismodegib, a clinically used anticancer drug reported to distort smell perception in patients. The ciliary phenotype of Smo inhibition is haploinsufficient, cell autonomous, and correlates with the accumulation of OR-containing putative transport vesicles in the cytosol. The Smo-dependent OR transport route works in parallel with a low basal transport of vesicle containing both ORs and other olfactory transduction components. These findings both define a physiological function of Hedgehog signaling in olfaction and provide an important evolutionary link between olfaction and the requirement of a ciliary compartment for Hedgehog signaling.

Keywords: Hedgehog pathway; Smoothened; cilia transport; odorant receptors; vismodegib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Cilia / drug effects
  • Cilia / metabolism*
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Hedgehog Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Pyridines / pharmacology
  • Receptors, Odorant / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Smoothened Receptor / metabolism

Substances

  • Anilides
  • Hedgehog Proteins
  • HhAntag691
  • Pyridines
  • Receptors, Odorant
  • Smoothened Receptor