Abstract
Key points The transduction of sound into electrical signals occurs at the hair bundles atop sensory hair cells in the cochlea, by means of mechanosensitive ion channels, the mechano‐electrical transducer (MET) channels.The MET currents decline during steady stimuli; this is termed adaptation and ensures they always work within the most sensitive part of their operating range, responding best to rapidly changing (sound) stimuli.In this study we used a mouse model (Snell's waltzer) for hereditary deafness in humans that has a mutation in the gene encoding an unconventional myosin, myosin VI, which is present in the hair bundles.We found that in the absence of myosin VI the MET current fails to acquire its characteristic adaptation as the hair bundles develop.We propose that myosin VI supports the acquisition of adaptation by removing key molecules from the hair bundle that serve a temporary, developmental role. Mutations in Myo6, the gene encoding the (F‐actin) minus end‐directed unconventional myosin, myosin VI, cause hereditary deafness in mice (Snell's waltzer) and humans. In the sensory hair cells of the cochlea, myosin VI is expressed in the cell bodies and along the stereocilia that project from the cells’ apical surface. It is required for maintaining the structural integrity of the mechanosensitive hair bundles formed by the stereocilia. In this study we investigate whether myosin VI contributes to mechano‐electrical transduction. We report that Ca2+‐dependent adaptation of the mechano‐electrical transducer (MET) current, which serves to keep the transduction apparatus operating within its most sensitive range, is absent in outer and inner hair cells from homozygous Snell's waltzer mutant mice, which fail to express myosin VI. The operating range of the MET channels is also abnormal in the mutants, resulting in the absence of a resting MET current. We found that cadherin 23, a component of the hair bundle's transient lateral links, fails to be downregulated along the length of the stereocilia in maturing Myo6 mutant mice. MET currents of heterozygous littermates appear normal. We propose that myosin VI, by removing key molecules from developing hair bundles, is required for the development of the MET apparatus and its Ca2+‐dependent adaptation.
Highlights
Myo6 was one of the first deafness genes identified (Avraham et al 1995)
We first sought to establish the basic properties of the mechano-electrical transducer (MET) currents of cochlear hair cells of Snell’s waltzer mice, concentrating on outer hair cell (OHC) because inner hair cell (IHC) are more difficult to approach for hair bundle stimulation and patch clamp recording during the first postnatal week
For eight P4–P6 OHCs the resting open probability of the MET current increased from 5.3 ± 0.8% at −84 mV to 19 ± 2% at +86 mV (P < 0.0001, paired t test)
Summary
Mutations of the gene encoding myosin VI, one of a number of unconventional myosins, are associated with dominant progressive (Melchionda et al 2001) and recessive congenital (Ahmed et al 2003) deafness in humans. Mice homozygous for the Snell’s waltzer mutation, a 130-bp deletion in the Myo gene resulting in a functional null mutation, are deaf and exhibit vestibular dysfunction associated with progressive degeneration of the sensory epithelium in the cochlea and vestibular organs (Avraham et al 1995). The hair cells of Snell’s waltzer mutant mice have no detectable myosin VI and appear to form normally during embryonic development. Similar abnormalities of the hair bundles are seen in mutant Tailchaser mice in which myosin VI is present but, due to a dominant point mutation, unable to move processively (Hertzano et al 2008; Pylypenko et al 2015). Motile myosin VI is required for maintaining the organization of the hair bundle during its postnatal maturation
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