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Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from  Pcdh15 av3J   ( av3J ),  Pcdh15 av6J   ( av6J ) and  Cdh23 v2J   ( v2J ) mice. The  av3J  and  v2J  mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for  Pcdh15  and  Cdh23 , respectively, and  av6J  mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in  av3J/av3J  and  v2J/v2J  mice. In contrast, only mild-to-moderate bundle disruption is evident in the  av6J/av6J  mice. Hair cells from  av3J/av3J  mice are unaffected by aminoglycosides and fail to load with [ 3 H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from  av6J/av6J  mice load with both FM1-43 and [ 3 H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the  av3J/av3J  and  v2J/v2J  mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in  av6J / av6J  mice, substantially reduced numbers of links in the  av3J/av3J  mice and virtually none in the  v2J/v2J  mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the  av3J / av3J  and  v2J / v2J  mice and a reduction in  av6J / av6J  mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction.

Mutations in Protocadherin 15 and Cadherin 23 Affect Tip Links and Mechanotransduction in Mammalian Sensory Hair Cells