Abstract
Hearing and vestibular function depend on mechanosensory staircase collections of hair cell stereocilia, which are produced from microvillus-like precursors as their parallel actin bundle scaffolds increase in diameter and elongate or shorten. Hair cell stereocilia contain multiple classes of actin-bundling protein, but little is known about what each class contributes. To investigate the roles of the espin class of actin-bundling protein, we used a genetic approach that benefited from a judicious selection of mouse background strain and an examination of the effects of heterozygosity. A congenic jerker mouse line was prepared by repeated backcrossing into the inbred CBA/CaJ strain, which is known for excellent hearing and minimal age-related hearing loss. We compared stereocilia in wild-type CBA/CaJ mice, jerker homozygotes that lack espin proteins owing to a frameshift mutation in the espin gene, and jerker heterozygotes that contain reduced espin levels. The lack of espins radically impaired stereociliary morphogenesis, resulting in stereocilia that were abnormally thin and short, with reduced differential elongation to form a staircase. Mean stereociliary diameter did not increase beyond ∼0.10–0.14 µm, making stereocilia ∼30%–60% thinner than wild type and suggesting that they contained ∼50%–85% fewer actin filaments. These characteristics indicate a requirement for espins in the appositional growth and differential elongation of the stereociliary parallel actin bundle and fit the known biological activities of espins in vitro and in transfected cells. The stereocilia of jerker heterozygotes showed a transient proximal-distal tapering suggestive of haploinsufficiency and a slowing of morphogenesis that revealed previously unrecognized assembly steps and intermediates. The lack of espins also led to a region-dependent degeneration of stereocilia involving shortening and collapse. We conclude that the espin actin-bundling proteins are required for the assembly and stabilization of the stereociliary parallel actin bundle.
Highlights
A stunning example of cytoskeleton-mediated morphogenesis is the formation of hair cell stereocilia, which act as primary mechanosensory detectors in the auditory and vestibular systems [1,2]
The changes in size appear to be driven by matching alterations in the dimensions of an underlying molecular scaffold consisting of a bundle of actin filaments cross-linked by actin-bundling proteins
In the absence of espins, stereocilia do not increase in diameter or complete their elongation, but instead bend, shorten, and disappear
Summary
A stunning example of cytoskeleton-mediated morphogenesis is the formation of hair cell stereocilia, which act as primary mechanosensory detectors in the auditory and vestibular systems [1,2]. Highly precise staircase collections of stereocilia are produced from microvillus-like precursors as their parallel actin bundle scaffolds selectively undergo an increase in diameter, through the addition of more actin filaments to the parallel actin bundle, and their constituent actin filaments elongate or shorten [4,5]. The dimensions of stereocilia vary in a remarkably regular way, within a given collection, and according to hair cell type and position in the cochlea or vestibular system [7,8,9,10]. This attests to an impressive degree of spatial precision in actincytoskeletal regulation. A growing list of deaf mutant mice with malformed stereocilia demonstrates the importance of stereociliary morphogenesis to hair cell mechanoelectrical signal transduction [11,12]
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