Transgenic Tmc2 expression preserves inner ear hair cells and vestibular function in mice lacking Tmc1

Yukako Asai,Carl Nist-Lund,Alice Galvin,Victoria A Lukashkina,Gwenaelle S G Géléoc,Hong Zhu,Wu Zhou,Andrei N Lukashkin,Jeffrey R Holt,Ian J Russell,Bifeng Pan,Tianwen Chen

doi:10.1038/s41598-018-28958-x

Yukako Asai, Carl Nist-Lund + Show 10 more

Open Access

https://doi.org/10.1038/s41598-018-28958-x

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Abstract

Recent work has demonstrated that transmembrane channel-like 1 protein (TMC1) is an essential component of the sensory transduction complex in hair cells of the inner ear. A closely related homolog, TMC2, is expressed transiently in the neonatal mouse cochlea and can enable sensory transduction in Tmc1-null mice during the first postnatal week. Both TMC1 and TMC2 are expressed at adult stages in mouse vestibular hair cells. The extent to which TMC1 and TMC2 can substitute for each other is unknown. Several biophysical differences between TMC1 and TMC2 suggest these proteins perform similar but not identical functions. To investigate these differences, and whether TMC2 can substitute for TMC1 in mature hair cells, we generated a knock-in mouse model allowing Cre-inducible expression of Tmc2. We assayed for changes in hair cell sensory transduction and auditory and vestibular function in Tmc2 knockin mice (Tm[Tmc2]) in the presence or absence of endogenous Tmc1, Tmc2 or both. Our results show that expression of Tm[TMC2] restores sensory transduction in vestibular hair cells and transiently in cochlear hair cells in the absence of TMC1. The cellular rescue leads to recovery of balance but not auditory function. We conclude that TMC1 provides some additional necessary function, not provided by TMC2.

Highlights

Sensory hair cells of the inner ear convert mechanical signals into electrical signals by means of a sensory transduction complex[1,2] that resides at the tips of stereocilia[3]
When mice were crossed with Gfi1Cre mice, recombination was observed in all IHCs and a mosaic green fluorescent protein (GFP) pattern was seen in OHCs both at P16 and 8 weeks (Fig. 1B)
Are transmembrane channel-like 1 protein (TMC1) and TMC2 complementary, redundant, or neither? Genetic redundancy associated with functional redundancy has led to generation of double or triple knockout models for numerous studies[14,15,16]

Summary

Introduction

Sensory hair cells of the inner ear convert mechanical signals into electrical signals by means of a sensory transduction complex[1,2] that resides at the tips of stereocilia[3]. Analysis of sensory transduction currents in hair cells of mice lacking only Tmc[1] or only Tmc[2] revealed nearly normal responses during the first postnatal week[7,8]. We assayed for changes in hair cell sensory transduction and auditory and vestibular function in the developing and mature Cre-recombined targeted knock-in Tmc[2] mice (referred to as Tm[Tmc2]) in presence or absence of endogenous Tmc[1], Tmc[2], or both. Tm[Tmc2] mice maintained normal sensory transduction in hair cells and expression of the Tm[Tmc2] gene in the absence of endogenous Tmc[1] and Tmc[2] preserved normal balance behavior, which is otherwise compromised in double Tmc1/Tmc2-null mice. Statistical analysis were performed using the independent t-test. *p < 0.05; **p < 0.01; ***p < 0.001

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