Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cadherin 23 is a component of the tip link in hair-cell stereocilia


Mechanoelectrical transduction, the conversion of mechanical force into electrochemical signals, underlies a range of sensory phenomena, including touch, hearing and balance. Hair cells of the vertebrate inner ear are specialized mechanosensors that transduce mechanical forces arising from sound waves and head movement to provide our senses of hearing and balance1,2; however, the mechanotransduction channel of hair cells and the molecules that regulate channel activity have remained elusive. One molecule that might participate in mechanoelectrical transduction is cadherin 23 (CDH23), as mutations in its gene cause deafness and age-related hearing loss3,4,5,6. Furthermore, CDH23 is large enough to be the tip link, the extracellular filament proposed to gate the mechanotransduction channel7. Here we show that antibodies against CDH23 label the tip link, and that CDH23 has biochemical properties similar to those of the tip link. Moreover, CDH23 forms a complex with myosin-1c, the only known component of the mechanotransduction apparatus8, suggesting that CDH23 and myosin-1c cooperate to regulate the activity of mechanically gated ion channels in hair cells.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: CDH23 expression in mouse inner ears.
Figure 2: CDH23 expression in hair cells.
Figure 3: Biochemical properties of CDH23.
Figure 4: Interaction of IL2R–CDH23 with MYO1C.


  1. 1

    Müller, U. & Evans, A. L. Mechanisms that regulate mechanosensory hair cell differentiation. Trends Cell Biol. 11, 334–342 (2001)

    Article  Google Scholar 

  2. 2

    Gillespie, P. G. & Walker, R. G. Molecular basis of mechanosensory transduction. Nature 413, 194–202 (2001)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Di Palma, F. et al. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nature Genet. 27, 103–107 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Bolz, H. et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nature Genet. 27, 108–112 (2001)

    CAS  Article  Google Scholar 

  5. 5

    Bork, J. M. et al. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am. J. Hum. Genet. 68, 26–37 (2001)

    CAS  Article  Google Scholar 

  6. 6

    Noben-Trauth, K., Zheng, Q. Y. & Johnson, K. R. Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nature Genet. 35, 21–23 (2003)

    CAS  Article  Google Scholar 

  7. 7

    Pickles, J. O., Comis, S. D. & Osborne, M. P. Cross-links between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction. Hear. Res. 15, 103–112 (1984)

    CAS  Article  Google Scholar 

  8. 8

    Holt, J. R. et al. A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells. Cell 108, 371–381 (2002)

    CAS  Article  Google Scholar 

  9. 9

    Corey, D. P. & Hudspeth, A. J. Kinetics of the receptor current in bullfrog saccular hair cells. J. Neurosci. 3, 962–976 (1983)

    CAS  Article  Google Scholar 

  10. 10

    Assad, J. A., Shepherd, G. M. & Corey, D. P. Tip-link integrity and mechanical transduction in vertebrate hair cells. Neuron 7, 985–994 (1991)

    CAS  Article  Google Scholar 

  11. 11

    Goodyear, R. J. & Richardson, G. P. A novel antigen sensitive to calcium chelation that is associated with the tip links and kinocilial links of sensory hair bundles. J. Neurosci. 23, 4878–4887 (2003)

    CAS  Article  Google Scholar 

  12. 12

    Takeichi, M. Cadherins: a molecular family important in selective cell–cell adhesion. Annu. Rev. Biochem. 59, 237–252 (1990)

    CAS  Article  Google Scholar 

  13. 13

    Boggon, T. J. et al. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296, 1308–1313 (2002)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Siemens, J. et al. The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions. Proc. Natl Acad. Sci. USA 99, 14946–14951 (2002)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Little, K. F. & Neugebauer, C. D. Interconnections between the stereovilli of the fish inner ear. II. Systematic investigation of saccular bundles from Rutilus rutilus (Teleostei). Cell Tissue Res. 242, 427–432 (1985)

    Article  Google Scholar 

  16. 16

    Pickles, J. O., Rouse, G. W. & von Perger, M. Morphological correlates of mechanotransduction in acousticolateral hair cells. Scan. Microsc. 5, 1115–1128 (1991)

    CAS  Google Scholar 

  17. 17

    Furness, D. N., Karkanevatos, A., West, B. & Hackney, C. M. An immunogold investigation of the distribution of calmodulin in the apex of cochlear hair cells. Hear. Res. 173, 10–20 (2002)

    CAS  Article  Google Scholar 

  18. 18

    Kachar, B., Parakkal, M., Kurc, M., Zhao, Y. & Gillespie, P. G. High-resolution structure of hair-cell tip links. Proc. Natl Acad. Sci. USA 97, 13336–13341 (2000)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Hasson, T. et al. Unconventional myosins in inner-ear sensory epithelia. J. Cell Biol. 137, 1287–1307 (1997)

    CAS  Article  Google Scholar 

  20. 20

    Zhao, Y., Yamoah, E. N. & Gillespie, P. G. Regeneration of broken tip links and restoration of mechanical transduction in hair cells. Proc. Natl Acad. Sci. USA 93, 15469–15474 (1996)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Osborne, M. P. & Comis, S. D. Action of elastase, collagenase and other enzymes upon linkages between stereocilia in the guinea-pig cochlea. Acta Otolaryngol. (Stockh.) 110, 37–45 (1990)

    CAS  Article  Google Scholar 

  22. 22

    Goodyear, R. & Richardson, G. The ankle-link antigen: an epitope sensitive to calcium chelation associated with the hair-cell surface and the calycal processes of photoreceptors. J. Neurosci. 19, 3761–3772 (1999)

    CAS  Article  Google Scholar 

  23. 23

    Gillespie, P. G., Wagner, M. C. & Hudspeth, A. J. Identification of a 120 kd hair-bundle myosin located near stereociliary tips. Neuron 11, 581–594 (1993)

    CAS  Article  Google Scholar 

  24. 24

    Söllner, C. et al. Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells. Nature advance online publication 31 March 2004 (doi:10.1038/nature02484)

  25. 25

    Boeda, B. et al. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J. 21, 6689–6699 (2002)

    CAS  Article  Google Scholar 

  26. 26

    Hudspeth, A. J. & Gillespie, P. G. Pulling springs to tune transduction: adaptation by hair cells. Neuron 12, 1–9 (1994)

    CAS  Article  Google Scholar 

  27. 27

    Garcia, J. A., Yee, A. G., Gillespie, P. G. & Corey, D. P. Localization of myosin-Iβ near both ends of tip links in frog saccular hair cells. J. Neurosci. 18, 8637–8647 (1998)

    CAS  Article  Google Scholar 

  28. 28

    Shepherd, G. M. G., Assad, J. A., Prarakkal, M., Kachar, B. & Corey, D. P. Movement of the tip-link attachment is correlated with adaptation in bullfrog saccular hair cells. J. Gen. Physiol. 98, 25A (1991)

    Google Scholar 

  29. 29

    Nagafuchi, A. & Takeichi, M. Cell binding function of E-cadherin is regulated by the cytoplasmic domain. EMBO J. 7, 3679–3684 (1988)

    CAS  Article  Google Scholar 

Download references


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.).

Author information



Corresponding author

Correspondence to Ulrich Müller.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Characterization of CDH23 antibodies. (JPG 41 kb)

Supplementary Figure 2

Characterization of CDH23 antibodies. (JPG 23 kb)

Supplementary Figure 3

Electron micrograph of the kinocilium and adjacent stereocilia of a bullfrog hair cell. (JPG 144 kb)

Supplementary Figure 4

CDH23 expressing cell lines. (JPG 31 kb)

Supplementary Figure 5

Colocalization of IL2R-CDH23 with MYO1C in COS cells. (JPG 47 kb)

Supplementary Figure Legends (DOC 21 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Siemens, J., Lillo, C., Dumont, R. et al. Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature 428, 950–955 (2004).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing