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Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane
Contributed by Christine Petit, October 23, 2019 (sent for review February 15, 2019; reviewed by Peter G. Barr-Gillespie and Guy P. Richardson)

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Significance
Patients lacking either otogelin or otogelin-like have congenital mild-to-moderate hearing impairment similar to that in patients lacking stereocilin. Stereocilin is associated with 2 types of links specific to the mechanosensitive antenna (stereocilia bundle) of cochlear outer hair cells: The horizontal top connectors joining stereocilia to one another and the attachment crowns coupling the tallest stereocilia to the tectorial membrane, an acellular structure overlying the sensory epithelium of the cochlea. By studying mutant mice lacking otogelin or otogelin-like and analyzing the distribution of these proteins, we show that they interact, directly or indirectly, with stereocilin to form the horizontal top connectors and tectorial membrane-attachment crowns, 2 structures likely satisfying similar mechanical requirements for cooperative stereociliary motion indispensable for optimal cochlear performance.
Abstract
The function of outer hair cells (OHCs), the mechanical actuators of the cochlea, involves the anchoring of their tallest stereocilia in the tectorial membrane (TM), an acellular structure overlying the sensory epithelium. Otogelin and otogelin-like are TM proteins related to secreted epithelial mucins. Defects in either cause the DFNB18B and DFNB84B genetic forms of deafness, respectively, both characterized by congenital mild-to-moderate hearing impairment. We show here that mutant mice lacking otogelin or otogelin-like have a marked OHC dysfunction, with almost no acoustic distortion products despite the persistence of some mechanoelectrical transduction. In both mutants, these cells lack the horizontal top connectors, which are fibrous links joining adjacent stereocilia, and the TM-attachment crowns coupling the tallest stereocilia to the TM. These defects are consistent with the previously unrecognized presence of otogelin and otogelin-like in the OHC hair bundle. The defective hair bundle cohesiveness and the absence of stereociliary imprints in the TM observed in these mice have also been observed in mutant mice lacking stereocilin, a model of the DFNB16 genetic form of deafness, also characterized by congenital mild-to-moderate hearing impairment. We show that the localizations of stereocilin, otogelin, and otogelin-like in the hair bundle are interdependent, indicating that these proteins interact to form the horizontal top connectors and the TM-attachment crowns. We therefore suggest that these 2 OHC-specific structures have shared mechanical properties mediating reaction forces to sound-induced shearing motion and contributing to the coordinated displacement of stereocilia.
- outer hair cell
- hair bundle link
- horizontal top connector
- tectorial membrane-attachment crown
- otoacoustic emission
Footnotes
↵1C.P. and E.V. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: christine.petit{at}pasteur.fr or elisabeth.verpy{at}pasteur.fr.
Author contributions: P.A., C.P., and E.V. designed research; P.A., S.L.G., V.M., T.D., and E.V. performed research; P.A. and E.V. analyzed data; and P.A., J.-P.H., C.P., and E.V. wrote the paper.
Reviewers: P.G.B.-G., Oregon Health & Science University; and G.P.R., University of Sussex.
Competing interest statement: C.P. and G.P.R. are coauthors on a 2019 review article and coedited the volume in which it appears.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1902781116/-/DCSupplemental.
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