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Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells

Nature volume 449, pages 87–91 (2007)Cite this article

Abstract

Hair cells of the inner ear are mechanosensors that transduce mechanical forces arising from sound waves and head movement into electrochemical signals to provide our sense of hearing and balance. Each hair cell contains at the apical surface a bundle of stereocilia. Mechanoelectrical transduction takes place close to the tips of stereocilia in proximity to extracellular tip-link filaments that connect the stereocilia and are thought to gate the mechanoelectrical transduction channel1,2,3. Recent reports on the composition4,5,6,7,8, properties and function9,10,11 of tip links are conflicting29. Here we demonstrate that two cadherins that are linked to inherited forms of deafness in humans12,13,14,15 interact to form tip links. Immunohistochemical studies using rodent hair cells show that cadherin 23 (CDH23) and protocadherin 15 (PCDH15) localize to the upper and lower part of tip links, respectively. The amino termini of the two cadherins co-localize on tip-link filaments. Biochemical experiments show that CDH23 homodimers interact in trans with PCDH15 homodimers to form a filament with structural similarity to tip links. Ions that affect tip-link integrity and a mutation in PCDH15 that causes a recessive form of deafness16 disrupt interactions between CDH23 and PCDH15. Our studies define the molecular composition of tip links and provide a conceptual base for exploring the mechanisms of sensory impairment associated with mutations in CDH23 and PCDH15.

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Figure 1: Tip links are formed by CDH23 and PCDH15.
Figure 2: The extracellular CDH23 and PCDH15 domains form parallel homodimers.
Figure 3: CDH23 binds to PCDH15.
Figure 4: Analysis of interactions between CDH23 and PCDH15.

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Acknowledgements

We thank M. Sotomayor for discussions regarding cadherin ectodomain structure. We thank members of the Müller and Kachar laboratories for comments. This work was supported by the NIH (U.M., R.A.M., E.M.W.-K., and H.S., J.T., B.K. (intramural funding)). Negative staining TEM analysis was conducted at the National Resource of Automated Molecular Microscopy.

Author Contributions U.M. and B.K. supervised the project and contributed equally as co-senior authors. P.K and H.S. are co-first authors. H.S. and J.T. characterized the antibodies and carried out the experiments in Fig. 1 and Supplementary Figs 1, 2 and 3. P.K. carried out the experiments in Figs 2–4 and Supplementary Figs 1, 4, 5 and 6. P.K. provided the proteins for negative staining TEM, which was carried out by E.M.W.-K.

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Author notes

  1. Piotr Kazmierczak, Hirofumi Sakaguchi, Ulrich Müller and Bechara Kachar: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute Department of Cell Biology, The Scripps Research,

    Piotr Kazmierczak, Elizabeth M. Wilson-Kubalek, Ronald A. Milligan & Ulrich Müller

  2. Institute for Childhood and Neglected Disease, La Jolla, California 92037, USA,

    Piotr Kazmierczak & Ulrich Müller

  3. Laboratory of Cellular Biology, National Institute on Deafness and other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA,

    Hirofumi Sakaguchi, Joshua Tokita & Bechara Kachar

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  1. Piotr Kazmierczak
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Correspondence to Ulrich Müller or Bechara Kachar.

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Kazmierczak, P., Sakaguchi, H., Tokita, J. et al. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449, 87–91 (2007). https://doi.org/10.1038/nature06091

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