Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

Abstract

How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.

Species generalization and differences in Hedgehog pathway regulation of fungiform and circumvallate papilla taste function and somatosensation demonstrated with sonidegib

“…However when HPI treatment is discontinued, the TB return/regenerate in FP and CV in mouse 3 . We and others have shown that GG neurons and nerve fibers are a source of SHH in taste organs 3 , 21 , 35 . We also reported that after HPI, SHH+ expression remained in the GG soma and furthermore, after HPI there was no decrease in numbers of GG neurons that express SHH 3 .…”

“…2a , K18/Ki67). Because HH regulation of proliferation in mouse FP has been reported 3 , 21 we counted Ki67+ cells in FP apical and basal wall regions (Fig. 2a , Vehicle).…”

“…Mechanisms include HPI affects on proliferation, not by a general defect but by decreased proliferation particularly within the apical FP. Decreased proliferation within FP basal epithelial cells after HPI has been reported and TB cell death per se has been ruled out as a driving factor in TB cell loss 3 , 21 . A differentiation defect was noted, also, in the FP apical region 3 .…”

Onset of taste bud cell renewal starts at birth and coincides with a shift in SHH function

“…Neurally supplied SHH is not required for taste progenitor activation. In adult tongue, SHH is expressed by postmitotic taste precursor cells and gustatory sensory neurons of the VII th cranial ganglion, which together support continual TRC differentiation (Castillo-Azofeifa et al, 2017;Lu et al, 2018;Miura et al, 2003). However, embryonic taste placodes are not innervated at specification, hence the only early source of lingual SHH is placodal (Hall et al, 1999).…”

“…In adult tongue, by contrast, SHH promotes TRC differentiation. Genetic deletion or pharmacological inhibition of Hh pathway components in mice inhibits taste cell differentiation (Castillo-Azofeifa et al, 2017;Castillo-Azofeifa et al, 2018;Kumari et al, 2015;Lu et al, 2018), while forced SHH expression induces formation of ectopic taste buds comprising all 3 TRC types (Castillo et al, 2014).…”