title: The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing.
abstract: The precise assembly of inner ear hair cell stereocilia into rows of increasing height is critical for mechanotransduction and the sense of hearing. Yet, how the lengths of actin-based stereocilia are regulated remains poorly understood. Mutations of the molecular motor myosin 15 stunt stereocilia growth and cause deafness. We found that hair cells express two isoforms of myosin 15 that differ by inclusion of an 133-kDa N-terminal domain, and that these isoforms can selectively traffic to different stereocilia rows. Using an isoform-specific knockout mouse, we show that hair cells expressing only the small isoform remarkably develop normal stereocilia bundles. However, a critical subset of stereocilia with active mechanotransducer channels subsequently retracts. The larger isoform with the 133-kDa N-terminal domain traffics to these specialized stereocilia and prevents disassembly of their actin core. Our results show that myosin 15 isoforms can navigate between functionally distinct classes of stereocilia, and are independently required to assemble and then maintain the intricate hair bundle architecture.
authors: Department of Human Genetics, University of Michigan, Ann Arbor, United States.
authors: Qing
authors: http://orcid.org/0000-0002-8808-8523
authors: Q
authors: Fang
authors: Department of Physiology, University of Kentucky, Lexington, United States.
authors: Artur A
authors: AA
authors: Indzhykulian
authors: Department of Human Genetics, University of Michigan, Ann Arbor, United States.
authors: Mirna
authors: M
authors: Mustapha
authors: Laboratory of Molecular Genetics, National Institutes of Health, Bethesda, United States.
authors: Gavin P
authors: GP
authors: Riordan
authors: Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, United States.
authors: David F
authors: DF
authors: Dolan
authors: Laboratory of Molecular Genetics, National Institutes of Health, Bethesda, United States.
authors: Thomas B
authors: TB
authors: Friedman
authors: Laboratory of Molecular Genetics, National Institutes of Health, Bethesda, United States.
authors: Inna A
authors: IA
authors: Belyantseva
authors: Department of Physiology, University of Kentucky, Lexington, United States.
authors: Gregory I
authors: GI
authors: Frolenkov
authors: Department of Human Genetics, University of Michigan, Ann Arbor, United States.
authors: Sally A
authors: SA
authors: Camper
authors: Laboratory of Molecular Genetics, National Institutes of Health, Bethesda, United States.
authors: Jonathan E
authors: http://orcid.org/0000-0001-5531-8794
authors: JE
authors: Bird
mesh_terms: D000818:Animals; D007758:Ear, Inner / Q000502:physiology; D006198:Hair Cells, Auditory / Q000502:physiology; D006309:Hearing; D051379:Mice; D018345:Mice, Knockout; D009218:Myosins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D059547:Stereocilia / Q000378:metabolism* / Q000502:physiology*
chemical_list: C114013:Myo15 protein, mouse; D020033:Protein Isoforms; D009218:Myosins
keywords: actin; cell biology; deafness; hearing; inner ear; mouse; myosin; neuroscience; stereocilia