β-Actin and fascin-2 cooperate to maintain stereocilia length.

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Acoustic Stimulation, Actins, Aging, Animals, Benzofurans, Cadherins, Carrier Proteins, Electroencephalography, Estrogen Receptor alpha, Evoked Potentials, Auditory, Brain Stem, Female, Hair Cells, Auditory, Hearing Loss, High-Frequency, Male, Mice, Mice, Transgenic, Microfilament Proteins, Microscopy, Atomic Force, Mutation, Phenotype, Protein Binding, Quinolines, Stereocilia

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J Neurosci 2013 May 8; 33(19):8114-21.




Stereocilia are actin-based protrusions on auditory sensory hair cells that are deflected by sound waves to initiate the conversion of mechanical energy to neuronal signals. Stereocilia maintenance is essential because auditory hair cells are not renewed in mammals. This process requires both β-actin and γ-actin as knock-out mice lacking either isoform develop distinct stereocilia pathology during aging. In addition, stereocilia integrity may hinge on immobilizing actin, which outside of a small region at stereocilia tips turns over with a very slow, months-long half-life. Here, we establish that β-actin and the actin crosslinking protein fascin-2 cooperate to maintain stereocilia length and auditory function. We observed that mice expressing mutant fascin-2 (p.R109H) or mice lacking β-actin share a common phenotype including progressive, high-frequency hearing loss together with shortening of a defined subset of stereocilia in the hair cell bundle. Fascin-2 binds β-actin and γ-actin filaments with similar affinity in vitro and fascin-2 does not depend on β-actin for localization in vivo. Nevertheless, double-mutant mice lacking β-actin and expressing fascin-2 p.R109H have a more severe phenotype suggesting that each protein has a different function in a common stereocilia maintenance pathway. Because the fascin-2 p.R109H mutant binds but fails to efficiently crosslink actin filaments, we propose that fascin-2 crosslinks function to slow actin depolymerization at stereocilia tips to maintain stereocilia length. J Neurosci 2013 May 8; 33(19):8114-21.