The actin cytoskeleton in hair bundle development and hearing loss

The inner ear houses the auditory and vestibular end organs, which are responsible for the sensation of hearing and balance, respectively. Although these organs vary considerably in architectural complexity, from the 3D intricacy of the cochlea to the more planar maculae of the vestibular system, they all share a common transduction machinery necessary for sensory function. At the heart of sensory transduction are hair cells, which convert mechanical displacements into perturbations of hair cell receptor potential. To transduce mechanical stimuli originating from sound or accelerations, each individual hair cell assembles a complex sensory bundle consisting of approximately 100 stereocilia that elongates from its apical pole (Schwander et al., 2010). Within each hair bundle, stereocilia are precisely arranged into rows of graded heights and widths (Fig. 1A) and are interconnected by an array of extracellular links that merge them into a mechanically cohesive unit (Richardson and Petit 2019). Tip-link filaments, formed of proto-cadherin-15 (PCDH15) and cadherin-23 (CDH23), bridge between the tips of shorter stereocilia (row 2 + 3) to the shaft of the nearest taller stereocilia neighbor (Kazmierczak et al. 2007). Displacement of the hair bundle towards the tallest row tensions tip links and gates mechanoelectrical (MET) channels located on these shorter stereocilia rows (Qiu and Müller, 2022). The overall architecture of the hair bundle is essential for the MET apparatus to be optimally stimulated by sound and accelerations. Highlighting the exquisite precision of this system, this architecture ensures detection of sub-nanometer hair bundle displacements at the threshold of hearing.

Unlike their name implies, stereocilia are not true cilia assembled from microtubules. Instead, they are actin-based organelles that develop from microvillus-like precursors using a complex program of elongation and thickening (Barr-Gillespie, 2015). The actin cytoskeleton is central to this process, forming the structural core within each stereocilium defining its size, shape and mechanical properties (Fig. 1B). Stereocilia vary tremendously throughout the mammalian inner ear, ranging from a few microns long in the cochlea to over 100 microns long in the vestibular organs. Stereocilia further vary in size and length depending on their position within each sensory organ; this variation is particularly evident in the cochlea where stereocilia lengths scale along the tonotopic axis. Stereocilia lengths are further tuned within each hair bundle to establish the graded heights of the staircase architecture. This spectrum of stereocilia shapes and sizes are reproduced during development to within tight tolerances, revealing the presence of a precise and tunable cytoskeletal assembly template. How this template is specified at a molecular level remains an enduring question. A substantial number of proteins necessary for establishing stereocilia architecture have now been identified, providing the component parts-list for this mechanism. Perhaps unsurprisingly, this parts-list is dominated by actin and actin-associated proteins, confirming their indispensable role in stereocilia assembly and sensory transduction (see Table 1 and Fig. 2). In this review, we explore the fundamental properties of the actin cytoskeleton, and how these proteins are harnessed to enable the development, plasticity and long-term structural integrity of stereocilia; processes that are indispensable for sensory function.

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