Partial Requirement of Endothelin Receptor B in Spiral Ganglion Neurons for Postnatal Development of Hearing

Michiru Ida-Eto,Nobutaka Ohgami,Machiko Iida,Ichiro Yajima,Mayuko Y Kumasaka,Kazutaka Takaiwa,Takashi Kimitsuki,Michihiko Sone,Tsutomu Nakashima,Toyonori Tsuzuki,Shizuo Komune,Masashi Yanagisawa,Masashi Kato

doi:10.1074/jbc.m111.236802

Abstract

Impairments of endothelin receptor B (Ednrb/EDNRB) cause the development of Waardenburg-Shah syndrome with congenital hearing loss, hypopigmentation, and megacolon disease in mice and humans. Hearing loss in Waardenburg-Shah syndrome has been thought to be caused by an Ednrb-mediated congenital defect of melanocytes in the stria vascularis (SV) of inner ears. Here we show that Ednrb expressed in spiral ganglion neurons (SGNs) in inner ears is required for postnatal development of hearing in mice. Ednrb protein was expressed in SGNs from WT mice on postnatal day 19 (P19), whereas it was undetectable in SGNs from WT mice on P3. Correspondingly, Ednrb homozygously deleted mice (Ednrb(-/-) mice) with congenital hearing loss showed degeneration of SGNs on P19 but not on P3. The congenital hearing loss involving neurodegeneration of SGNs as well as megacolon disease in Ednrb(-/-) mice were markedly improved by introducing an Ednrb transgene under control of the dopamine β-hydroxylase promoter (Ednrb(-/-);DBH-Ednrb mice) on P19. Neither defects of melanocytes nor hypopigmentation in the SV and skin in Ednrb(-/-) mice was rescued in the Ednrb(-/-);DBH-Ednrb mice. Thus, the results of this study indicate a novel role of Ednrb expressed in SGNs distinct from that in melanocytes in the SV contributing partially to postnatal hearing development.

Highlights

Waardenburg syndrome (WS)3 involves hearing loss and hypopigmentation
There was no information in that report about the role of endothelin receptor B (Ednrb) in spiral ganglion neurons (SGNs), which serve as peripheral neurons in inner ears for the auditory system, it was shown in the present study that Ednrb protein is expressed in SGNs
Because gaps between SGNs and Schwann cells and vacuolar degeneration have been shown to be neurodegeneration markers [13, 25], our results suggest that decreased cell density of SGNs in EdnrbϪ/Ϫ mice was caused by neurodegeneration

Summary

Introduction

Waardenburg syndrome (WS)3 involves hearing loss and hypopigmentation. The incidence of WS is 1/10,000 –20,000 people [1]. Impairments of Ednrb/EDNRB have been shown to cause embryonic defects of melanocytes and enteric ganglion neurons derived from the neural crest, resulting in hypopigmentation, megacolon disease, and congenital hearing loss.

Results

Conclusion