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Stereocilin-deficient mice reveal the origin of cochlear waveform distortions


Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions1. These distortions reflect nonlinear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility2. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus3. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. Because both cochlear amplification and distortion originate from the outer hair cells-one of the two types of sensory receptor cells-it has been speculated that they stem from a common mechanism. Here we show that the nonlinearity underlying cochlear waveform distortions relies on the presence of stereocilin, a protein defective in a recessive form of human deafness4. Stereocilin was detected in association with horizontal top connectors5,6,7, lateral links that join adjacent stereocilia within the outer hair cell's hair bundle. These links were absent in stereocilin-null mutant mice, which became progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, we conclude that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic nonlinear behaviour of the mechanoelectrical transducer channel.

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Figure 1: Hearing sensitivity and frequency tuning in stereocilin-null versus wild-type mice.
Figure 2: Waveform distortions in wild-type and stereocilin-null mice.
Figure 3: OHC hair-bundle morphology in P14 wild-type and stereocilin-null mice.
Figure 4: Immunodetection of stereocilin in wild-type and Tecta ΔENT/ΔENT OHCs.


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We thank M. Lenoir, S. Guadagnini and M.-C. Prévost for advice on SEM; E. Perret and P. Roux for advice on confocal microscopy, S. Chardenoux, S. Nouaille and A. Mallet for technical help, Y. Lallemand for providing us with PGK-Crem mice, N. Michalski for help with figure drawing and J. Boutet de Monvel for critical reading of the manuscript. This work was supported by the European Commission FP6 Integrated Project EuroHear, Fondation Raymonde et Guy Strittmatter, Région Ile-de-France (Programme Sésame), and the Wellcome Trust.

Author Contributions C.P. and P.A. contributed equally as co-senior authors. D.W. and M.L. are co-second authors. D.W. and G.H. produced the Strc knockout mice. P.A. conducted the auditory tests. M.L. performed the SEM experiments on wild type, Strc-/- and TectaΔENT/ΔENT mice, with help from C.H. G.M.L. carried out the SEM experiments in the mouse models of Usher syndrome. E.V. performed the immunofluorescence studies with help from C.H., and the RT–PCR analysis. G.P.R. and R.J.G. carried out the transmission electron microscopy analysis. E.V. supervised the stereocilin expression studies and the characterization of the morphological anomalies in the Strc knockout mice. C.P. supervised the whole project with help from G.P.R. and in collaboration with P.A. for the physiological studies. E.V., J.-P.H., G.P.R., P.A. and C.P. prepared the manuscript.

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Correspondence to Elisabeth Verpy or Christine Petit.

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Verpy, E., Weil, D., Leibovici, M. et al. Stereocilin-deficient mice reveal the origin of cochlear waveform distortions. Nature 456, 255–258 (2008).

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