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Review
. 2023 Sep 1:436:108817.
doi: 10.1016/j.heares.2023.108817. Epub 2023 May 26.

The actin cytoskeleton in hair bundle development and hearing loss

Jinho Park  1 , Jonathan E Bird  2
Affiliations
Review

The actin cytoskeleton in hair bundle development and hearing loss

Jinho Park et al. Hear Res. .

Abstract

Inner ear hair cells assemble mechanosensitive hair bundles on their apical surface that transduce sounds and accelerations. Each hair bundle is comprised of ∼ 100 individual stereocilia that are arranged into rows of increasing height and width; their specific and precise architecture being necessary for mechanoelectrical transduction (MET). The actin cytoskeleton is fundamental to establishing this architecture, not only by forming the structural scaffold shaping each stereocilium, but also by composing rootlets and the cuticular plate that together provide a stable foundation supporting each stereocilium. In concert with the actin cytoskeleton, a large assortment of actin-binding proteins (ABPs) function to cross-link actin filaments into specific topologies, as well as control actin filament growth, severing, and capping. These processes are individually critical for sensory transduction and are all disrupted in hereditary forms of human hearing loss. In this review, we provide an overview of actin-based structures in the hair bundle and the molecules contributing to their assembly and functional properties. We also highlight recent advances in mechanisms driving stereocilia elongation and how these processes are tuned by MET.

Keywords: Actin; Actin binding protein; Deafness; Hair bundle; Hearing loss; Stereocilia.

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Figures

Fig. 1.
Fig. 1.
The actin cytoskeleton in hair cell stereocilia. (A) Scanning electron microscopy (SEM) of a cochlear hair cell, demonstrating the graded stereocilia sizes that contribute to the hair bundle architecture. Row 1 stereocilia are the tallest, with the shorter rows 2 + 3 having active MET channels gated by bundle deflection. Scale bar is 2 μm. (B) Transmission electron microscopy (TEM) of a sectioned stereocilia revealing its highly ordered core of actin filaments. The rootlet structure is darkly stained and penetrates into the stereocilia and cuticular plate. Scale bar is 250 nm. (C) TEM image of the stereocilia taper region demonstrating how the rootlet deforms during stereocilia deflection. (D) Structural model of an actin monomer (PDB: 1J6Z) with subdomains 1–4 and the nucleotide binding cleft labeled. The DNase I binding loop (D-loop) forms part of the interface between adjacent protomers in a filament. (E) Structural model of an actin filament (PDB: 6BNO) with an individual monomer highlighted in red. Actin filaments have structural polarity with a fast-growing barbed end and a pointed end where depolymerization occurs. Images reproduced with permission from: (A) Beurg M, et al. (2006) Journal of Neuroscience 26 (43) 10,992–11,000, DOI: 10.1523/JNEUROSCI.2188-06.2006, Copyright © 2006, Society for Neuroscience. (B) Mogensen et al. (2007) Cell Motil Cytoskeleton 64 (7): 496–508, DOI: 10.1002/cm.20199. Copyright © 2007, Wiley-Liss, Inc. (C) Furness et al. (2008) Journal of Neuroscience 28 (25): 6342–53, DOI: 10.1523/JNEUROSCI.1154-08.2008, Copyright © 2008, Society for Neuroscience. Molecular structures were rendered in VMD and Chimera.
Fig. 2.
Fig. 2.
Distribution of actin-associated proteins in hair cell stereocilia. (A) Cartoon of a mammalian hair cell bundle with specific stereocilia zones expanded in panels B–E. Each stereocilium consists of thousands of parallel actin filaments that are cross-linked together and decorated by actin-associated proteins to form the structural core and provide signaling to control polymerization / depolymerization. (B) In the tallest row 1 stereocilia, MYO3A, MYO3B and MYO15A-2 traffic and deliver critical molecular cargoes to the tip. MYO3A / B transports ESPN-1 whilst MYO15A-2 delivers the elongation complex (EPS8, WHRN, GPSM2, GNAI3) that is hypothesized to form a biomolecular condensate as part of the tip density. Actin polymerization is concentrated at the stereocilia tip, where actin filament barbed ends are polarized and available for turnover during stereocilia development and maturation. (C) Mechanoelectrical transduction (MET) channels, comprised of TMC1/2, TMIE and CIB2 (LHFPL5 is not shown) are localized to the lower tip link density (LTLD) at the tips of shorter row 2 and 3 stereocilia that are also enriched with actin filament barbed ends. The tip link protein PCDH15 inserts into the LTLD. At the other end of the tip link is the upper tip link density (UTLD) that associates with CDH23 via MYO7A, USH1C (Harmonin) and USH1G (Sans). Barbed ends of row 2 actin filaments are capped with a combination of TWF2, EPS8L2 and CAPZB. Actin severing proteins DSTN1/CFL1 can uncover actin filament barbed ends to promote actin polymerization, and this process is stimulated by MET. CIB2 may interact with actin filaments via WHRN and MYO15A-1, although this interaction remains to be demonstrated in vivo. (D) Actin-binding proteins (PLS1, FSCN2, ESPN, XIRP2) extensively cross-link actin filaments to increase stiffness of the stereocilia core (left panel). Following mechanical trauma, XIRP2 and new γ-actin (ACTG1) monomers are incorporated to repair the stereocilia core. (E) TRIOBP-4 and TRIOBP-5 cross-link actin filaments to form a dense rootlet that stabilizes stereocilia in the actin meshwork of the cuticular plate. Additional proteins, including TPRN, GRXCR2, RIPOR2, CLIC5 and MYO6 localize to the taper region, where actin filament pointed ends terminate and the stereocilia diameter reduces.
Fig. 3.
Fig. 3.
MET currents adaptively shape the stereocilia cytoskeleton. (A) Scanning electron microscopy (SEM) of hair bundles treated with a pharmacological inhibitor of the MET channel (amiloride), leaving tip-links intact. After 24 h of treatment, row 2 and 3 stereocilia with active MET channels have abnormal architecture, indicating a significant remodeling of the actin cytoskeleton. (B) Fluorescence confocal imaging of permeabilized hair cells incubated with rhodamine-labeled actin monomers to reveal the presence of barbed ends available to support polymerization. Free barbed ends are normally concentrated at the tips of row 2, but this is reduced following pharmacological blockade of MET currents using tubocurarine. Scale bars are 5 μm. Images reproduced with permission from: (A) Vélez-Ortega et al. (2017) eLife 6:e24661, DOI:10.7554/eLife.24661. (B) McGrath et al. (2021) Current Biology 31 (6): 1141–1153, DOI: 10.1016/j.cub.2020.12.006.
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