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Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells

Abstract

Hair cells have highly organized bundles of apical projections, or stereocilia, that are deflected by sound and movement. Displacement of stereocilia stretches linkages at the tips of stereocilia that are thought to gate mechanosensory channels1. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing2. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction3,4. Here we show that the defects in sputnik mutants are caused by mutations in cadherin 23 (cdh23). Mutations in Cdh23 also cause deafness and vestibular defects in mice and humans5,6,7,8,9, and the protein is present in hair bundles10,11. We show that zebrafish Cdh23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputniktc317e larvae. Moreover, tip links are absent in larvae carrying weak alleles of cdh23 that affect mechanotransduction but not hair bundle integrity. We conclude that Cdh23 is an essential tip link component required for hair-cell mechanotransduction.

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Figure 1: Positional cloning of sputnik and identification of the mutations in cdh23.
Figure 2: Confocal images of splaying of inner ear hair bundles in mutant sputnik larvae and cdh23 morphants (5 d.p.f.).
Figure 3: Localization of Cdh23 to hair bundles and absence of tip links in sputnik mutants.

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Acknowledgements

We thank U. Schönberger, A. Hruscha and members of the electron microscopy laboratory (especially H. Schwarz) at the Max-Planck-Institut für Entwicklungsbiologie for their technical support and advice. This work was supported by funding from the SFB430 and DFG.

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Correspondence to Teresa Nicolson.

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Supplementary information

Supplementary Figure 1

In situ hybridization with cdh23 sense and antisense riboprobes. (JPG 53 kb)

Supplementary Figure 2

Degree of splaying or disorganization of hair bundles in mutants carrying the strong allele tc317e. (JPG 85 kb)

Supplementary Figure 3

Rare examples of tip link material or tenting of stereocilia in mutants carrying the weak allele te370e or strong allele tc317e. (JPG 50 kb)

Supplementary Figure Legends (DOC 21 kb)

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Söllner, C., Rauch, GJ., Siemens, J. et al. Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells. Nature 428, 955–959 (2004). https://doi.org/10.1038/nature02484

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