Mechanotransduction in mouse inner ear hair cells requires transmembrane channel–like genes

TLDR

Inner ear hair cells convert mechanical stimuli such as sound, gravity, and head movement into electrical signals via mechanotransduction initiated by opening of cation channels at stereocilia tips. The study aimed to determine whether the transmembrane channel–like genes Tmc1 and Tmc2 contribute to mechanotransduction in mice, given that TMC1 mutations cause hearing loss. Loss of Tmc1 alone caused deafness, loss of Tmc2 alone had no effect, but double mutants lacked mechanotransduction despite normal hair cell structure; expressing either TMC1 or TMC2 restored mechanotransduction, demonstrating that both proteins are essential components of the mechanotransduction complex and that persistent TMC2 expression may preserve vestibular function in humans with TMC1‑related hearing loss.

Abstract

Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel–like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1Δ mice) were deaf and those with a deletion of Tmc2 (Tmc2Δ mice) were phenotypically normal, Tmc1ΔTmc2Δ mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. Expression of either exogenous TMC1 or TMC2 rescued mechanotransduction in Tmc1ΔTmc2Δ mutant hair cells. Our results indicate that TMC1 and TMC2 are necessary for hair cell mechanotransduction and may be integral components of the mechanotransduction complex. Our data also suggest that persistent TMC2 expression in vestibular hair cells may preserve vestibular function in humans with hearing loss caused by TMC1 mutations.