Abstract
The Hedgehog (Hh) pathway has regulatory roles in maintaining and restoring lingual taste organs, the papillae and taste buds, and taste sensation. Taste buds and taste nerve responses are eliminated if Hh signaling is genetically suppressed or pharmacologically inhibited, but regeneration can occur if signaling is reactivated within the lingual epithelium. Whereas Hh pathway disruption alters taste sensation, tactile and cold responses remain intact, indicating that Hh signaling is modality-specific in regulation of tongue sensation. However, although Hh regulation is essential in taste, the basic biology of pathway controls is not fully understood. With recent demonstrations that sonic hedgehog (Shh) is within both taste buds and the innervating ganglion neurons/nerve fibers, it is compelling to consider Hh signaling throughout the tongue and taste organ cell and tissue compartments. Distinctive signaling centers and niches are reviewed in taste papilla epithelium, taste buds, basal lamina, fibroblasts and lamellipodia, lingual nerves, and sensory ganglia. Several new roles for the innervation in lingual Hh signaling are proposed. Hh signaling within the lingual epithelium and an intact innervation each is necessary, but only together are sufficient to sustain and restore taste buds. Importantly, patients who use Hh pathway inhibiting drugs confront an altered chemosensory world with loss of taste buds and taste responses, intact lingual touch and cold sensation, and taste recovery after drug discontinuation.
Highlights
The ligand is within chorda tympani and glossopharyngeal nerve fibers that distribute in the fungiform (FP) and circumvallate (CV) papilla connective tissue cores, respectively [3,4,6]
Whereas it was shown that Hh signaling within the lingual epithelium is essential for taste bud (TB) maintenance, the long-documented nerve-dependent degeneration and regeneration of TB had demonstrated that nerves clearly are essential, too, in TB homeostasis [40,41,42]
Sonic hedgehog (Shh) expression could not attract innervation to K8+ cells. Conclusions from these recent papers have been varied and include the following: (a) TB and nerve sources of Shh are necessary to maintain FP/TB because Shh loss from only one source has minimal effect on TB maintenance and the epithelial and neural sources of Shh function ‘redundantly’ [4]; (b) epithelial Shh deletion does not result in TB loss [3,4], whereas neural Shh contributes to long term maintenance of TB and is required for regeneration of TB [3]; (c) Hh signaling in the lingual epithelium is essential for TB morphologic and sensory homeostasis and regeneration [6,9]; and (d) even sustained neural Hh signaling alone, from intact GG and chorda tympani (CT) fibers, cannot maintain homeostasis or initiate reconstitution/regeneration of TB in the face of epithelial Hh pathway suppression [6,9]
Summary
Sonic hedgehog (Shh) is a principal and essential regulatory molecule in taste bud (TB) homeostasis and taste sensation, demonstrated with multiple approaches, including: When Shh signaling is activated [1,2,3], inhibited [3,4,5,6,7,8], suppressed [9], or if key components are genetically deleted [3,4,6,9], in turn, the TBs are altered and taste nerve responses to chemical stimuli are eliminated [5,6,7]. Deleting BDNF at E14.5 did not alter taste placode number or Shh expression [32], supporting the data that taste placode formation does not require sensory nerves [16] Throughout these developmental studies, there emerged and continued an emphasis on Hh signaling as a major morphogen pathway in the taste system. To learn whether the Hh pathway could regulate the constantly renewing TB cells in adult rodents and thereby support homeostasis in a sensory organ system with receptor cells that continually turnover [37], Hh signaling was altered pharmacologically and genetically in the whole body or in epithelial tissues [5,6,7,9].
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