Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex

• Published in: Nature communications Vol. 11; no. 1; pp. 2066 - 15
• Main Authors: Li, Sihan, Mecca, Andrew, Kim, Jeewoo, Caprara, Giusy A., Wagner, Elizabeth L., Du, Ting-Ting, Petrov, Leonid, Xu, Wenhao, Cui, Runjia, Rebustini, Ivan T., Kachar, Bechara, Peng, Anthony W., Shin, Jung-Bum
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.04.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 14; 14/19; 14/63; 45/41; 631/337; 631/378; 631/378/2619/1533; 631/80; 64/110; 64/60; 9/74; Amino Acid Sequence; Animals; Base Sequence; Blindness; Cell Cycle Proteins - metabolism; Cochlea; Cytoskeletal Proteins - metabolism; Deafness; Gene Deletion; Hair; Hair cells; Hair Cells, Auditory, Inner - metabolism; Hair Cells, Auditory, Inner - ultrastructure; Hearing loss; Hearing Loss - metabolism; Hearing Loss - pathology; Hearing protection; Humanities and Social Sciences; Isoforms; Mechanotransduction; Mechanotransduction, Cellular; Mice, Inbred C57BL; multidisciplinary; Mutation; Myosin; Myosin VIIa - chemistry; Myosin VIIa - genetics; Myosin VIIa - metabolism; Outer hair cells; Protein Isoforms - metabolism; Protein Transport; Science; Science (multidisciplinary); Sensitizing; Stereocilia - metabolism; Stereocilia - ultrastructure; Tensioning
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15936-z

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. How the ear achieves its remarkable sensitivity is still not fully understood. In this study, the authors demonstrate that the deafness protein myosin-VIIa and its isoforms are essential for tensioning the tip link, thereby sensitizing the auditory receptor cell’s mechanotransduction process.