The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration

Mohi Ahmed,Elysia James,Andrea Streit,Ravindra Singh Prajapati,Ruth Moon,M Albert Basson

doi:10.1038/s42003-021-02788-6

Abstract

Neurons and sensory cells are particularly vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission. The mechanisms that protect them from stress-induced death and degeneration remain elusive. Here we show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Mechanistically, we demonstrate that CHD7 controls the expression of major stress pathway components. In its absence, hair cells are hypersensitive, dying rapidly after brief exposure to stress inducers, suggesting that sound at the onset of hearing triggers their degeneration. In humans, CHD7 haploinsufficiency causes CHARGE syndrome, a disorder affecting multiple organs including the ear. Our findings suggest that CHD7 mutations cause developmentally silent phenotypes that predispose cells to postnatal degeneration due to a failure of protective mechanisms.

Highlights

Neurons and sensory cells are vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission
As the hair cells lack the capacity to regenerate, oxidative stress caused by loud noise, ageing, or ototoxicity leads to cell death and permanent hearing loss[15,16,17,18,19]
Hair cells appeared normal at P8 (n = 10/10; Fig. S2a, b) suggesting that Chd[7] function may not be required for their development

Summary

Introduction

Neurons and sensory cells are vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission. We show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Inner hair cells are responsible for sound perception, while outer hair cells modulate the sound amplitude[13] They are innervated by type I and type II spiral ganglion neurons, respectively, which project to the auditory nuclei in the brain stem[14]. As the hair cells (and spiral ganglion neurons) lack the capacity to regenerate, oxidative stress caused by loud noise, ageing, or ototoxicity leads to cell death and permanent hearing loss[15,16,17,18,19]

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Conclusion