TY - JOUR
T1 - Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells
AU - Tübingen 2000 Screen Consortium
AU - Söllner, Christian
AU - Nicolson, Teresa
AU - Rauch, Gerd Jörg
AU - Geisler, Robert
AU - Schuster, Stephan C.
AU - Siemens, Jan
AU - Müller, Ulrich
AU - Nicolson, Teresa
AU - Van Bebber, F.
AU - Busch-Nentwich, E.
AU - Dahm, R.
AU - Frank, O.
AU - Frohnhöfer, H. G.
AU - Geiger, H.
AU - Gilmour, D.
AU - Holley, S.
AU - Hooge, J.
AU - Jülich, D.
AU - Knaut, H.
AU - Maderspacher, F.
AU - Maischein, H. M.
AU - Neumann, C.
AU - Nüsslein-Volhard, C.
AU - Roehl, H.
AU - Schönberger, U.
AU - Seiler, C.
AU - Sidi, S.
AU - Sonawane, M.
AU - Wehner, A.
AU - Erker, P.
AU - Habeck, H.
AU - Hagner, U.
AU - Hennen Kaps, C. E.
AU - Kirchner, A.
AU - Koblizek, T.
AU - Langheinrich, U.
AU - Loeschke, C.
AU - Metzger, C.
AU - Nordin, R.
AU - Odenthal, J.
AU - Pezzuti, M.
AU - Schlombs, K.
AU - de Santana-Stamm, J.
AU - Trowe, T.
AU - Vacun, G.
AU - Walderich, B.
AU - Walker, A.
AU - Weiler, C.
N1 - Funding Information:
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.
Funding Information:
Acknowledgements We thank R. Kemler for E-cadherin clones; M. Senften for L929 cells expressing E-cadherin; T. Hasson, B. Ranscht and H. C. VanSteenhouse for technical advice; and A. Kralli, L. Stowers and A. Patapoutian for critical reading of the manuscript. J.S. was supported by a fellowship from the Boehringer Ingelheim Fonds; A.R. by a C. J. Martin Fellowship from the National Health and Medical Research Council (Australia). This work was supported by grants from the NIDCD and NEI (U.M, P.G.G. and D.S.W.).
PY - 2004/4/29
Y1 - 2004/4/29
N2 - 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 channels. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction. 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, and the protein is present in hair bundles. 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.
AB - 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 channels. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction. 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, and the protein is present in hair bundles. 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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U2 - 10.1038/nature02484
DO - 10.1038/nature02484
M3 - Letter
C2 - 15057246
AN - SCOPUS:84905556082
SN - 0028-0836
VL - 428
SP - 955
EP - 959
JO - Nature
JF - Nature
IS - 6986
ER -