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

A Kumari,L Li,Y Yokota,R M Bradley,C M Mistretta

doi:10.1038/s41598-018-34399-3

Abstract

Species generalization in the profound, modality-specific effects of Hedgehog pathway inhibition (HPI) in taste organ homeostasis and sensation is shown. With the HPI, cancer drug sonidegib, we demonstrate that the rat taste system, in addition to mouse, is regulated by Hedgehog signaling. After sonidegib treatment for 16–36 days in rat, there is loss of taste buds (TB) in soft palate, in fungiform (FP) and circumvallate papillae (CV), and elimination of taste responses from chorda tympani and glossopharyngeal nerves. The retained innervation in FP and CV during HPI cannot sustain TB. Responses to tactile stimuli are not altered, and temperature responses are reduced only after 28 days treatment, demonstrating modality-specific effects. Rat FP and neural effects are similar to those in mouse whereas TB and neural response effects from the rat CV are much more severe. When recovery is introduced in mouse after prolonged, 48 days HPI, the TB in CV are restored whereas those in FP are not. Overall, Hedgehog signaling regulation is shown to generalize to the rat taste system, and the modality-specific controls in taste organ sensation are affirmed. The reported, debilitating taste disturbances in patients who use HPI drugs can be better understood based on these data.

Highlights

In mouse, we had demonstrated required roles for Hedgehog (HH) signaling in taste organ homeostasis and the elemental effects of HH pathway inhibition (HPI) on adult taste system integrity[1,2,3]
taste buds (TB) in fungiform papillae (FP) and taste responses are eliminated by Hedgehog pathway inhibition (HPI) with sonidegib in rat
We present effects on each FP/TB Type over treatment times (Fig. 1b)

Summary

Introduction

We had demonstrated required roles for Hedgehog (HH) signaling in taste organ homeostasis and the elemental effects of HH pathway inhibition (HPI) on adult taste system integrity[1,2,3]. Taste buds (TB) in the fungiform papillae (FP) and taste responses from the chorda tympani (CT) nerve are eliminated after administration of the HPI drug sonidegib for 16 days in mouse[2,3]. Functional sensory effects in the mouse have been shown only for anterior tongue FP/TB/CT, but not studied for the soft palate, or the circumvallate (CV) papilla/TB responses from the glossopharyngeal nerve. Study of FP and CV papillae, soft palate, TB, and neural responses after HPI addresses regulation of different taste systems by HH signaling. To test for HH signaling regulation of taste systems in rat, we gavaged animals with the HPI drug sonidegib, recorded from the CT or GL nerve, and determined effects on TB and on FP and CV structure, and on TB in soft palate. Effects in mouse CV/GL taste system were less profound than those in rat

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Results

Conclusion