Abstract
Mutations in myosin-VIIa (MYO7A) cause Usher syndrome type 1, characterized by combined deafness and blindness. MYO7A is proposed to function as a motor that tensions the hair cell mechanotransduction (MET) complex, but conclusive evidence is lacking. Here we report that multiple MYO7A isoforms are expressed in the mouse cochlea. In mice with a specific deletion of the canonical isoform (Myo7a-ΔC mouse), MYO7A is severely diminished in inner hair cells (IHCs), while expression in outer hair cells is affected tonotopically. IHCs of Myo7a-ΔC mice undergo normal development, but exhibit reduced resting open probability and slowed onset of MET currents, consistent with MYO7A’s proposed role in tensioning the tip link. Mature IHCs of Myo7a-ΔC mice degenerate over time, giving rise to progressive hearing loss. Taken together, our study reveals an unexpected isoform diversity of MYO7A expression in the cochlea and highlights MYO7A’s essential role in tensioning the hair cell MET complex.
Highlights
Mutations in myosin-VIIa (MYO7A) cause Usher syndrome type 1, characterized by combined deafness and blindness
Using a previously characterized antibody[21], we examined the localization of MYO7A at the upper tip-link density (UTLD) and the stereocilia base
Comparing WT and Myo7a-ΔC mice (Supplementary Fig. 4), we found that the creep was greater in Myo7a-ΔC mice with a larger contribution of the slower creep component (two-way ANOVA: A2—magnitude of the slower creep component p = 0.043; (A2/(A1 + A2)—relative magnitude of the slower creep component, p = 2.2e−4; (A1 + A2)/y0— relative magnitude of the creep compared with the total displacement of the hair bundle, p = 1.0e−4)
Summary
Mutations in myosin-VIIa (MYO7A) cause Usher syndrome type 1, characterized by combined deafness and blindness. IHCs of Myo7a-ΔC mice undergo normal development, but exhibit reduced resting open probability and slowed onset of MET currents, consistent with MYO7A’s proposed role in tensioning the tip link. The adaptor proteins USH1G (sans) and USH1C (harmonin)[21,23,24,25] presumably provide the scaffold by which the F-actin-bound motor connects to the upper end of the tip link Consistent with this notion, mutations in harmonin were shown to affect the resting Po of the MET channel[24]. In genetically engineered mice with a specific deletion of the canonical MYO7A isoform (Myo7a-ΔC mouse), MYO7A levels are severely reduced in IHCs, but the hair bundle develops normally This mouse model provided an avenue to test the role of MYO7A in hair cell MET function. The changes in MET current properties, hair bundle morphology and hearing function in the Myo7a-ΔC mouse are in support for a direct role of MYO7A in tensioning the hair cell MET complex
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