Mechanotransduction current is essential for stability of the transducing stereocilia in mammalian auditory hair cells

Vélez-Ortega, A. Catalina; Freeman, Mary J; Indzhykulian, Artur A.; Grossheim, Jonathan M; Frolenkov, Gregory I.

doi:10.7554/elife.24661

Cited by 83 publications

(100 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A difference in Ca 2+ selectivity may be crucial: P Ca /P Cs = 1.8 for the anomalous PIEZO2 channels but P Ca /P Cs = 5 for the MT channel in OHCs . Ca 2+ influx through the hair cell channel is essential for generating adaptation, and has also been proposed to be necessary for regulating actin polymerization at the stereociliary tips and hair bundle organization (Velez-Ortega et al 2017). This requirement is presumably the reason that, in order to direct bundle maturation, cochlear hair cells acquire mechanotransducer channels early in development, well before the onset of hearing, which occurs around postnatal day 12 in mice.…”

Section: Resultsmentioning

confidence: 99%

PIEZO2 as the anomalous mechanotransducer channel in auditory hair cells

Beurg

Fettiplace

2017

The Journal of Physiology

View full text Add to dashboard Cite

Throughout postnatal maturation of the mouse inner ear, cochlear hair cells display at least two types of mechanically gated ion channel: normal mechanotransducer (MT) channels at the tips of the stereocilia, activated by tension in interciliary tip links, and anomalous mechanosensitive (MS) channels on the top surface of the cells. The anomalous MS channels are responsible for the reverse‐polarity current that appears in mutants in which normal transduction is lost. They are also seen in wild‐type hair cells around birth, appearing 2 days earlier than normal MT channels, and being down‐regulated with the emergence of the normal channels. We review the evidence that the normal and anomalous channels are distinct channel types, which includes differences in localization, susceptibility to pharmacological agents, single‐channel conductance and Ca2+ permeability. The dichotomy is reinforced by the observation that the anomalous current is absent in cochlear cells of Piezo2‐null mice, even though the normal MT current persists. The anomalous current is suppressed by high intracellular Ca2+, suggesting that influx of the divalent ion via more Ca2+‐permeable normal MT channels inhibits the anomalous channels, thus explaining the temporal relationship between the two. Piezo2‐null mice have largely normal hearing, exhibiting up to 20 dB elevation in threshold in the acoustic brainstem response, so raising questions about the significance of PIEZO2 in the cochlea. Since the anomalous current declines with postnatal age, PIEZO2 may contribute to hair cell development, but it does not underlie the normal MT current. Its role in the development of hearing is not understood.

show abstract

Section: Resultsmentioning

confidence: 99%

PIEZO2 as the anomalous mechanotransducer channel in auditory hair cells

Beurg

Fettiplace

2017

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…It is noteworthy that an abnormal shortening of mechanotransducing stereocilia has also been reported in mice deficient for several components of the mechano‐electrical transduction machinery, namely the TMC1/TMC2 channel complex (Kawashima et al , ), TMIE (Zhao et al , ), LHFPL5 (Xiong et al , ), and sans or cadherin‐23 (Caberlotto et al , ) and PCDH15 (Pepermans et al , ). Furthermore, Velez‐Ortega and colleagues recently showed that reducing mechano‐electrical transduction currents in wild‐type mouse or rat hair cells, using pharmacological channel blockers or disruption of tip links, leads to reduction in the height of the middle and shortest row “transducing” stereocilia (Velez‐Ortega et al , ). Thus, it is possible that the stereocilia phenotype observed in clarinet mutant mice is a downstream consequence of a defect in mechano‐electrical transduction.…”

Section: Discussionmentioning

confidence: 99%

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

et al. 2019

View full text Add to dashboard Cite

Hearing relies on mechanically gated ion channels present in the actin‐rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound‐receptive structure is limited. Utilizing a large‐scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early‐onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non‐syndromic progressive hearing loss. Our in‐depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin‐2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin‐2 leads to loss of mechano‐electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin‐2 in mammalian hearing, providing insights into the interplay between mechano‐electrical transduction and stereocilia maintenance.

show abstract

“…Together, these data point to a particular requirement for β-actin in maintaining stereocilia length. As with Actb knockout, blocking mechanotransduction also results in degeneration of the shorter rows of stereocilia, which can subsequently regrow when mechanotransduction is restored (29). Considering that the mechanotransductive apparatus is under constant mechanical stress, one possibility is that damage and repair during aging results in cycles of stereocilia shortening and regrowth (30).…”

Section: Discussionmentioning

confidence: 99%

Essential nucleotide- and protein-dependent functions ofActb/β-actin

Patrinostro

Roy

Lindsay

et al. 2018

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

View full text Add to dashboard Cite

The highly similar cytoplasmic β- and γ-actins differ by only four functionally similar amino acids, yet previous in vitro and in vivo data suggest that they support unique functions due to striking phenotypic differences between and null mouse and cell models. To determine whether the four amino acid variances were responsible for the functional differences between cytoplasmic actins, we gene edited the endogenous mouse locus to translate γ-actin protein. The resulting mice and primary embryonic fibroblasts completely lacked β-actin protein, but were viable and did not present with the most overt and severe cell and organismal phenotypes observed with gene knockout. Nonetheless, the edited mice exhibited progressive high-frequency hearing loss and degeneration of actin-based stereocilia as previously reported for hair cell-specific knockout mice. Thus, β-actin protein is not required for general cellular functions, but is necessary to maintain auditory stereocilia.

show abstract

Mechanotransduction current is essential for stability of the transducing stereocilia in mammalian auditory hair cells

Cited by 83 publications

References 58 publications

PIEZO2 as the anomalous mechanotransducer channel in auditory hair cells

PIEZO2 as the anomalous mechanotransducer channel in auditory hair cells

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

Essential nucleotide- and protein-dependent functions ofActb/β-actin

Contact Info

Product

Resources

About