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

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 t...

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Bibliographic Details
Published in:Nature (London) 2007-09, Vol.449 (7158), p.87-91
Main Authors: Müller, Ulrich, Wilson-Kubalek, Elizabeth M, Milligan, Ronald A, Kachar, Bechara, Tokita, Joshua, Kazmierczak, Piotr, Sakaguchi, Hirofumi
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Cadherins - deficiency
Cadherins - genetics
Cadherins - metabolism
Cell Line
Cells
Deafness
Deafness - genetics
Dimerization
Ears & hearing
Electrochemistry
Genes, Recessive - genetics
Guinea Pigs
Hair
Hair Cells, Auditory - cytology
Hair Cells, Auditory - metabolism
Humanities and Social Sciences
Humans
Ions
letter
Mice
multidisciplinary
Mutation
Mutation - genetics
Protein Binding
Protein Precursors - genetics
Protein Precursors - metabolism
Rodents
Science
Science (multidisciplinary)
Signal transduction
Sound
Sound waves
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Summary: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 channel. Recent reports on the composition, properties and function of tip links are conflicting. Here we demonstrate that two cadherins that are linked to inherited forms of deafness in humans 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 deafness 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature06091