RESUMO
Stereocilia are actin-based protrusions on auditory and vestibular sensory cells that are required for hearing and balance. They convert physical force from sound, head movement or gravity into an electrical signal, a process that is called mechanoelectrical transduction. This function depends on the ability of sensory cells to grow stereocilia of defined lengths. These protrusions form a bundle with a highly precise geometry that is required to detect nanoscale movements encountered in the inner ear. Congenital or progressive stereocilia degeneration causes hearing loss. Thus, understanding stereocilia hair bundle structure, development, and maintenance is pivotal to understanding the pathogenesis of deafness. Stereocilia cores are made from a tightly packed array of parallel, crosslinked actin filaments, the length and stability of which are regulated in part by myosin motors, actin crosslinkers and capping proteins. This review aims to describe stereocilia actin regulation in the context of an emerging "tip turnover" model where actin assembles and disassembles at stereocilia tips while the remainder of the core is exceptionally stable.
Assuntos
Actinas/genética , Células Ciliadas Auditivas/ultraestrutura , Células Ciliadas Vestibulares/ultraestrutura , Audição/fisiologia , Mecanotransdução Celular , Estereocílios/ultraestrutura , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Actinas/metabolismo , Animais , Proteínas Relacionadas a Caderinas , Caderinas/genética , Caderinas/metabolismo , Surdez/patologia , Surdez/fisiopatologia , Expressão Gênica , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Vestibulares/metabolismo , Camundongos , Modelos Biológicos , Morfogênese , Miosinas/genética , Miosinas/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Estabilidade Proteica , Estereocílios/metabolismoRESUMO
Stereocilia on auditory sensory cells are actin-based protrusions that mechanotransduce sound into an electrical signal. These stereocilia are arranged into a bundle with three rows of increasing length to form a staircase-like morphology that is required for hearing. Stereocilia in the shorter rows, but not the tallest row, are mechanotransducing because they have force-sensitive channels localized at their tips. The onset of mechanotransduction during mouse postnatal development refines stereocilia length and width. However, it is unclear how actin is differentially regulated between stereocilia in the tallest row of the bundle and the shorter, mechanotransducing rows. Here, we show actin turnover is increased at the tips of mechanotransducing stereocilia during bundle maturation. Correspondingly, from birth to postnatal day 6, these stereocilia had increasing amounts of available actin barbed ends, where monomers can be added or lost readily, as compared with the non-mechanotransducing stereocilia in the tallest row. The increase in available barbed ends depended on both mechanotransduction and MYO15 or EPS8, which are required for the normal specification and elongation of the tallest row of stereocilia. We also found that loss of the F-actin-severing proteins ADF and cofilin-1 decreased barbed end availability at stereocilia tips. These proteins enriched at mechanotransducing stereocilia tips, and their localization was perturbed by the loss of mechanotransduction, MYO15, or EPS8. Finally, stereocilia lengths and widths were dysregulated in Adf and Cfl1 mutants. Together, these data show that actin is remodeled, likely by a severing mechanism, in response to mechanotransduction.
Assuntos
Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Mecanotransdução Celular , Estereocílios/metabolismo , Animais , Feminino , Audição , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Mechanosensory bundles on auditory sensory cells are composed of stereocilia that grow in rows of decreasing height. This pattern depends on the specification of the eventual tallest row, then the assignment of distinct molecular identities to the shorter rows. Mechanotransduction refines and maintains row identity, thus instructing the form of the bundle.