Hedgehog signaling regulates ciliary localization of mouse odorant receptors

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.

Olfactory receptor neurons express olfactory marker protein but not calpain 5 from the same genomic locus

“…Primary cilia are widely found in many cells, including neural cells and blood cells, operating as cellular antennae for development via Sonic hedgehog (Shh) signaling [39–43]. Shh in the olfactory mucus and epithelium is involved in axon growth, ciliary extension and functional localization of AC3 and odorant receptors in the cilia, though the loss of Shh is irrelevant to OMP expression [44–47]; OMP is initially expressed before the functional maturation of ORNs. Unlike other terminally differentiated neurons, ORNs periodically undergo turnover [48], and OMP remains in the ORNs, even during the apoptotic stage [49].…”

Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling

“…Our results now suggest a role for motile cilia in noncanonical HH signaling. In addition, a recent report suggested the HH signaling components localize odorant receptors in mouse olfactory cilia ( 48 ); olfactory cilia have a 9 + 2 axoneme, but lack dynein arms and are immotile ( 30 ). Thus, during evolution, HH signaling components and cilia may have been adapted for a variety of functions, with variations in cilia type and the function of HH signaling components.…”

Neuromodulation, Short-Term and Long-Term Plasticity in Corticothalamic and Hippocampal Neuronal Networks

“…Non-canonical Wnt maintains basal NMDAR mediated synaptic transmission via the tyrosine kinase-like orphan receptor 2 (RoR2) (Cerpa et al 2015). Hh-signaling in the olfactory system can regulate the expression of olfactory receptors both in adult fruit fly, Drosophila Melanogaster, and in adult mice (Sanchez et al 2016, Maurya et al 2017. (Hall et al 2014).…”

“…Additionally, the effect of Hh signaling on immature hippocampus has revealed that Hh promotes growth of presynaptic terminals and increasing the frequency of spontaneous vesicle release (Mitchell et al 2012). In adult fruit flies, Drosophila Melanogaster, Hh-signaling regulates the surface expression of odorant receptors in the fly antenna (Sanchez et al 2016) and controls the expression of odorant receptors and the odorant response in adult mice olfactory system (Maurya et al 2017). These findings triggered our interests to investigate if Hh-signaling could regulate receptor expression in mature central neurons as in the olfactory system.…”