Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing

Chen, Tingfang; Rohacek, Alex M; Caporizzo, Matthew A.; Nankali, Amir; Smits, Jeroen J.; Oostrik, Jaap; Lanting, Cornelis P.; Küçük, Erdi; Gilissen, Christian; Kamp, Jiddeke M. van de; Pennings, Ronald J.E.; Rakowiecki, Staci M.; Kaestner, Klaus H.; Ohlemiller, Kevin K.; Oghalai, John S.; Kremer, Hannie; Prosser, Benjamin L.; Epstein, Douglas J.

doi:10.1016/j.devcel.2021.04.017

Cited by 24 publications

(23 citation statements)

References 87 publications

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“…The thinner F-actin bands in SCs of the developing cochlea may be important for convergent extension, cell intercalation, and other morphogenic movements that are essential to the development of the organ of Corti’s precise patterning ( Cohen et al, 2020 ). The circumferential F-actin bands of Deiters cells and pillar cells thicken postnatally ( Burns et al, 2013 ), and the epithelial surface becomes stiffer ( Szarama et al, 2012 ; Chen et al, 2021 ), but it remains to be determined whether SCs in the cochleae of older mice become insensitive to blebbistatin treatment.…”

Section: Discussionmentioning

confidence: 99%

Stiffening of Circumferential F-Actin Bands Correlates With Regenerative Failure and May Act as a Biomechanical Brake in the Mammalian Inner Ear

Rudolf

Andreeva²,

Kim³

et al. 2022

Front. Cell. Neurosci.

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The loss of inner ear hair cells causes permanent hearing and balance deficits in humans and other mammals, but non-mammals recover after supporting cells (SCs) divide and replace hair cells. The proliferative capacity of mammalian SCs declines as exceptionally thick circumferential F-actin bands develop at their adherens junctions. We hypothesized that the reinforced junctions were limiting regenerative responses of mammalian SCs by impeding changes in cell shape and epithelial tension. Using micropipette aspiration and atomic force microscopy, we measured mechanical properties of utricles from mice and chickens. Our data show that the epithelial surface of the mouse utricle stiffens significantly during postnatal maturation. This stiffening correlates with and is dependent on the postnatal accumulation of F-actin and the cross-linker Alpha-Actinin-4 at SC-SC junctions. In chicken utricles, where SCs lack junctional reinforcement, the epithelial surface remains compliant. There, SCs undergo oriented cell divisions and their apical surfaces progressively elongate throughout development, consistent with anisotropic intraepithelial tension. In chicken utricles, inhibition of actomyosin contractility led to drastic SC shape change and epithelial buckling, but neither occurred in mouse utricles. These findings suggest that species differences in the capacity for hair cell regeneration may be attributable in part to the differences in the stiffness and contractility of the actin cytoskeletal elements that reinforce adherens junctions and participate in regulation of the cell cycle.

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Section: Discussionmentioning

confidence: 99%

Stiffening of Circumferential F-Actin Bands Correlates With Regenerative Failure and May Act as a Biomechanical Brake in the Mammalian Inner Ear

Rudolf

Andreeva²,

Kim³

et al. 2022

Front. Cell. Neurosci.

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“…Microtubules and bundled actin filaments together are essential for the mechanical properties of the apical surfaces of sensory hair cells and supporting cells ( 37 ). This interplay was studied using molecular mediators such as latrunculin A, jasplakinolide, blebbistatin, taxol, and nocodazole ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, GAS2 (growth-arrest-specific 2), a protein with microtubule and F-actin–binding domains, was shown to be expressed in pillar and DCs colocalizing specifically with microtubules. Absence of GAS2 significantly reduced the stiffness of the supporting cell phalangeal processes ( 37 ). These observations raise additional questions as to the individual functions of other cytoskeleton-associated proteins of hair cells and supporting cells such as tropomyosin, spectrin, β-actin, γ-actin, espin, prestin, and tubulin and the effects of pathogenic variants in the corresponding genes on the cellular structures that might also contribute to the radial stiffness gradients we report here.…”

Section: Discussionmentioning

confidence: 99%

Unbalanced bidirectional radial stiffness gradients within the organ of Corti promoted by TRIOBP

Babahosseini

Belyantseva

Yousaf

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Hearing depends on intricate morphologies and mechanical properties of diverse inner ear cell types. The individual contributions of various inner ear cell types into mechanical properties of the organ of Corti and the mechanisms of their integration are yet largely unknown. Using sub-100-nm spatial resolution atomic force microscopy (AFM), we mapped the Young’s modulus (stiffness) of the apical surface of the different cells of the freshly dissected P5–P6 cochlear epithelium from wild-type and mice lacking either Trio and F-actin binding protein (TRIOBP) isoforms 4 and 5 or isoform 5 only. Variants of TRIOBP are associated with deafness in human and in Triobp mutant mouse models. Remarkably, nanoscale AFM mapping revealed unrecognized bidirectional radial stiffness gradients of different magnitudes and opposite orientations between rows of wild-type supporting cells and sensory hair cells. Moreover, the observed bidirectional radial stiffness gradients are unbalanced, with sensory cells being stiffer overall compared to neighboring supporting cells. Deafness-associated TRIOBP deficiencies significantly disrupted the magnitude and orientation of these bidirectional radial stiffness gradients. In addition, serial sectioning with focused ion beam and backscatter scanning electron microscopy shows that a TRIOBP deficiency results in ultrastructural changes of supporting cell apical phalangeal microfilaments and bundled cortical F-actin of hair cell cuticular plates, correlating with messenger RNA and protein expression levels and AFM stiffness measurements that exposed a softening of the apical surface of the sensory epithelium in mutant mice. Altogether, this additional complexity in the mechanical properties of the sensory epithelium is hypothesized to be an essential contributor to frequency selectivity and sensitivity of mammalian hearing.

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“…In mice, Gas2 is expressed in supporting cells but also in the stria vascularis from the post-natal cochlea and its disruption causes hearing loss in mice and human. 58 Taken together, these findings suggest that dysfunctions in the stria vascularis involve a large range of molecular mechanisms, globally impacting strial function.…”

Section: Gtex Tissue Enrichment Analysis and Cell-type Specificity Of...mentioning

confidence: 93%

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Trpchevska,

Freidin,

Broer

et al. 2022

The American Journal of Human Genetics

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Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing

Cited by 24 publications

References 87 publications

Stiffening of Circumferential F-Actin Bands Correlates With Regenerative Failure and May Act as a Biomechanical Brake in the Mammalian Inner Ear

Stiffening of Circumferential F-Actin Bands Correlates With Regenerative Failure and May Act as a Biomechanical Brake in the Mammalian Inner Ear

Unbalanced bidirectional radial stiffness gradients within the organ of Corti promoted by TRIOBP

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

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