CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells

Arnaud P J Giese,Mary J Freeman,Zubair M Ahmed,Adam C Goldring,Gregory I Frolenkov,Yi-Quan Tang,Andrew Parker,William R Schafer,Saima Riazuddin,Steve D M Brown,Robert Fettiplace,Ghanshyam P Sinha,Michael R Bowl

doi:10.1038/s41467-017-00061-1

Abstract

Inner ear hair cells detect sound through deflection of stereocilia, the microvilli-like projections that are arranged in rows of graded heights. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. Here, we have characterized two mutant mouse lines, one lacking calcium and integrin-binding protein 2 and one carrying a human deafness-related Cib2 mutation, and show that both are deaf and exhibit no mechanotransduction in auditory hair cells, despite the presence of tip links that gate the mechanotransducer channels. In addition, mechanotransducing shorter row stereocilia overgrow in hair cell bundles of both Cib2 mutants. Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.

Highlights

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We report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib[2] mutations
We recorded distortion product otoacoustic emission (DPOAE), a by-product of cochlear amplification that depends on the integrity of outer hair cells (OHCs)

Summary

Introduction

Right click to open a feedback form in a new tab to let us know how this document benefits you. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. At the lower end of the tip link, protocadherin 15 may interact with TMC1 and TMC26, the proposed core components of the mechano-electrical transduction (MET) complex[7] It is still a subject of debate whether TMC1 and TMC2 could form an ion channel and represent the pore-forming subunits of the MET channel[8,9,10]. We show that CIB2 interacts with the MET channel components TMC1 and TMC2, is essential for MET function and regulating the length of transducing shorter row stereocilia in mammalian auditory hair cells. We did not observe any changes of Cib[2] expression during the first postnatal week or differences in Cib[2] expression along the length of the cochlea (Fig. 1b, Supplementary Fig. 1b)

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Conclusion