1. Max-Planck-Institut für Entwicklungsbiologie, Spemannstrasse 35, 72076 Tübingen, Germany
2. Abteilung Genetik, Max-Planck-Institut für Entwicklungsbiologie, Spemannstrasse 35, 72076 Tübingen, Germany
3. AG Genomics & Signal transduction, Max-Planck-Institut für Entwicklungsbiologie, Spemannstrasse 35, 72076 Tübingen, Germany
4. The Scripps Research Institute, 10550 N. Torrey Pines Road, Mail Drop ICND222, La Jolla, California 92037, USA
5. Oregon Hearing Research Center and Vollum Institute, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
6. A list of members of the Tübingen 2000 Screen Consortium and their affiliations appears at the end of the paper

Correspondence to: Teresa Nicolson^1,5 Email: nicolson@ohsu.edu
The sequence has been deposited in GenBank under accession number AY530192.

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 mechanotransduction^{3, 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 humans^{5, 6, 7, 8, 9}, and the protein is present in hair bundles^{10, 11}. We show that zebrafish Cdh23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputnik^tc317e 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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