scholarly journals TRPV5, TRPV6, TRPM6, and TRPM7 do not contribute to hair-cell mechanotransduction

2017 ◽  
Author(s):  
Clive P. Morgan ◽  
Hongyu Zhao ◽  
Meredith LeMasurier ◽  
Wei Xiong ◽  
Bifeng Pan ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Auditory Function ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Cysteine Substitution ◽  
Tip Link ◽  
Transient Receptor ◽  
Receptor Channel

AbstractThe hair-cell mechanotransduction channel remains unidentified. We tested whether four transient receptor channel (TRP) family members, TRPV5, TRPV6, TRPM6, and TRPM7, participated in transduction. Using cysteine-substitution mouse knock-ins and methanethiosulfonate reagents selective for those alleles, we found that inhibition of TRPV5 or TRPV6 had no effect on transduction in mouse cochlear hair cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic cells, which suggested they could participate in transduction. Cochlear hair cell transduction was insensitive to shRNA knockdown ofTrpm6orTrpm7, however, and was not affected by manipulations of Mg2+, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in transduction, we showed that deletion of either or both of their genes selectively in hair cells had no effect on auditory function. We suggest that TRPV5, TRPV6, TRPM6, and TRPM7 are unlikely to be the pore-forming subunit of the hair-cell transduction channel.

scholarly journals Effects of cochlear hair cell ablation on spatial learning/memory

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Z. Jason Qian ◽  
Anthony J. Ricci
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Spatial Learning ◽  
Hair Cells ◽  
Noise Exposure ◽  
Memory Errors ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Cell Ablation ◽  
Spatial Learning Memory

AbstractCurrent clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30–60 and underwent the RAM assay during P90–120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.

Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells

Development ◽  
1998 ◽  
Vol 125 (4) ◽  
pp. 557-566 ◽  
Author(s):  
T. Self ◽  
M. Mahony ◽  
J. Fleming ◽  
J. Walsh ◽  
S.D. Brown ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Usher Syndrome ◽  
Orthologous Gene ◽  
Cell Development ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Show Evidence ◽  
Myosin Viia ◽  
And Function

The mouse shaker-1 locus, Myo7a, encodes myosin VIIA and mutations in the orthologous gene in humans cause Usher syndrome type 1B or non-syndromic deafness. Myo7a is expressed very early in sensory hair cell development in the inner ear. We describe the effects of three mutations on cochlear hair cell development and function. In the Myo7a816SB and Myo7a6J mutants, stereocilia grow and form rows of graded heights as normal, but the bundles become progressively more disorganised. Most of these mutants show no gross electrophysiological responses, but some did show evidence of hair cell depolarisation despite the disorganisation of their bundles. In contrast, the original shaker-1 mutants, Myo7ash1, had normal early development of stereocilia bundles, but still showed abnormal cochlear responses. These findings suggest that myosin VIIA is required for normal stereocilia bundle organisation and has a role in the function of cochlear hair cells.

Polybrene: Observations on cochlear hair cell necrosis and minimal lentiviral transduction of cochlear hair cells

2015 ◽  
Vol 600 ◽  
pp. 164-170 ◽  
Author(s):  
Miaomiao Han ◽  
Dongzhen Yu ◽  
Qiang Song ◽  
Jiping Wang ◽  
Pin Dong ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Cell Necrosis ◽  
Cochlear Hair Cells ◽  
Lentiviral Transduction ◽  
Cochlear Hair Cell

Large Releasable Pool of Synaptic Vesicles in Chick Cochlear Hair Cells

2004 ◽  
Vol 91 (6) ◽  
pp. 2422-2428 ◽  
Author(s):  
Marc D. Eisen ◽  
Maria Spassova ◽  
Thomas D. Parsons
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Neurotransmitter Release ◽  
Metabotropic Glutamate Receptors ◽  
Cochlear Hair Cells ◽  
Metabotropic Glutamate ◽  
Cochlear Hair Cell ◽  
Cytoplasmic Vesicles ◽  
Vesicle Pool ◽  
Cell Synapse

Hearing requires the hair cell synapse to maintain notable temporal fidelity (≤1 ms) while sustaining neurotransmitter release for prolonged periods of time (minutes). Here we probed the properties and possible anatomical substrate of prolonged neurotransmitter release by using electrical measures of cell surface area as a proxy for neurotransmitter release to study hair cell exocytosis evoked by repetitive stimuli. We observed marked depression of exocytosis by chick tall hair cells. This exocytic depression cannot be explained by calcium current inactivation, presynaptic autoinhibition by metabotropic glutamate receptors, or postsynaptic receptor desensitization. Rather, cochlear hair cell exocytic depression resulted from the exhaustion of a functional vesicle pool. This releasable vesicle pool is large, totaling approximately 8,000 vesicles, and is nearly 10 times greater than the number of vesicles tethered to synaptic ribbons. Such a large functional pool suggests the recruitment of cytoplasmic vesicles to sustain exocytosis, important for maintaining prolonged, high rates of neural activity needed to encode sound.

scholarly journals Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia

2019 ◽  
Vol 28 (24) ◽  
pp. 4103-4112 ◽  
Author(s):  
Wu Li ◽  
Yong Feng ◽  
Anhai Chen ◽  
Taoxi Li ◽  
Sida Huang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Actin Cytoskeleton ◽  
Hearing Impairment ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Vestibular Function ◽  
Outer Hair Cells ◽  
Auditory Function ◽  
Cochlear Hair Cells

Abstract ELMOD3, an ARL2 GTPase-activating protein, is implicated in causing hearing impairment in humans. However, the specific role of ELMOD3 in auditory function is still far from being elucidated. In the present study, we used the CRISPR/Cas9 technology to establish an Elmod3 knockout mice line in the C57BL/6 background (hereinafter referred to as Elmod3−/− mice) and investigated the role of Elmod3 in the cochlea and auditory function. Elmod3−/− mice started to exhibit hearing loss from 2 months of age, and the deafness progressed with aging, while the vestibular function of Elmod3−/− mice was normal. We also observed that Elmod3−/− mice showed thinning and receding hair cells in the organ of Corti and much lower expression of F-actin cytoskeleton in the cochlea compared with wild-type mice. The deafness associated with the mutation may be caused by cochlear hair cells dysfunction, which manifests with shortening and fusion of inner hair cells stereocilia and progressive degeneration of outer hair cells stereocilia. Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment.

scholarly journals Activation of Wnt/β-catenin signaling to increase BMI1 by Licl attenuates the toxicity of cisplatin in the HEI-OC1 auditory cells

2021 ◽  
Author(s):  
Yingpeng Xu ◽  
Chen Sun ◽  
Chen Lu ◽  
Yaqing Liu ◽  
Ling Lu ◽  
...  
Keyword(s):  
Hair Cell ◽  
Cell Line ◽  
Hair Cells ◽  
Cell Apoptosis ◽  
Expression Level ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Bmi1 Expression ◽  
Signaling Activation ◽  
Gsk3 Inhibitor

Abstract Cisplatin is a very effective anti-tumor drug; nonetheless, it can induce cochlear hair cell apoptosis and ototoxicity in large doses. WNT/β-catenin signaling is also closely related to aging, embryonic development, and apoptosis. We establish a cisplatin-induced HEI-OC1 auditory cells model. WNT/β-catenin was activated by GSK3 inhibitor Licl to detect the expression level of each component of the WNT pathway and BMI1. The expression of BMI1 in the hair cell line model of HEI-OC1 cells induced by cisplatin was significantly reduced, and cell apoptosis was significantly reduced by increasing the expression level of cell line BMI through activating WNT/β-catenin signaling. Activation of WNT/β-catenin signaling to increase BMI1 expression can reduce the apoptosis of cochlear hair cells induced by cisplatin. BMI1 also has a protective effect on the ototoxicity of cisplatin.

Cochlear Hair Cell Stereocilia Loss in LP/J Mice with Bone Dysplasia of the Middle Ear

1989 ◽  
Vol 98 (6) ◽  
pp. 461-465 ◽  
Author(s):  
Richard A. Chole ◽  
Maggie Chiu
Keyword(s):  
Hair Cell ◽  
Middle Ear ◽  
Hair Cells ◽  
Inbred Mice ◽  
Bone Dysplasia ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Cochlear Hair Cells ◽  
Inner Hair Cells ◽  
Cochlear Hair Cell

LP/J inbred mice spontaneously develop bony lesions of the middle ear and otic capsule that are similar to those of human otosclerosis and tympanosclerosis. These mice also have progressive loss of hearing due to cochlear hair cell loss. The purpose of this study was to describe quantitatively the deterioration and loss of cochlear hair cells to serve as a basis for future experiments attempting to alter the course of this disorder. Cochleas from 37 LP/J inbred mice were examined by scanning electron microscopy. The stereocilia loss in the cochlea was evident as early as 15 weeks of age and progressed from the basal turn to the apex. Outer hair cells were affected more than inner hair cells. As outer hair cells deteriorated we observed fusion, bending, and breakage of stereocilia. There were no apparent differences in the mode of deterioration among the three rows of outer hair cells. Stereocilia fusion of inner hair cells occurred at an older age, and giant, elongated stereocilia were found in some of the animals.

scholarly journals The role of transmembrane channel–like proteins in the operation of hair cell mechanotransducer channels

2013 ◽  
Vol 142 (5) ◽  
pp. 493-505 ◽  
Author(s):  
Kyunghee X. Kim ◽  
Maryline Beurg ◽  
Carole M. Hackney ◽  
David N. Furness ◽  
Shanthini Mahendrasingam ◽  
...  
Keyword(s):  
Hair Cells ◽  
Hair Bundle ◽  
Wild Type ◽  
Cochlear Hair Cells ◽  
Transmembrane Channel ◽  
Protein Partners ◽  
Tip Link ◽  
Lower Permeability ◽  
Precise Role

Sound stimuli elicit movement of the stereocilia that make up the hair bundle of cochlear hair cells, putting tension on the tip links connecting the stereocilia and thereby opening mechanotransducer (MT) channels. Tmc1 and Tmc2, two members of the transmembrane channel–like family, are necessary for mechanotransduction. To assess their precise role, we recorded MT currents elicited by hair bundle deflections in mice with null mutations of Tmc1, Tmc2, or both. During the first postnatal week, we observed a normal MT current in hair cells lacking Tmc1 or Tmc2; however, in the absence of both isoforms, we recorded a large MT current that was phase-shifted 180°, being evoked by displacements of the hair bundle away from its tallest edge rather than toward it as in wild-type hair cells. The anomalous MT current in hair cells lacking Tmc1 and Tmc2 was blocked by FM1-43, dihydrostreptomycin, and extracellular Ca2+ at concentrations similar to those that blocked wild type. MT channels in the double knockouts carried Ca2+ with a lower permeability than wild-type or single mutants. The MT current in double knockouts persisted during exposure to submicromolar Ca2+, even though this treatment destroyed the tip links. We conclude that the Tmc isoforms do not themselves constitute the MT channel but are essential for targeting and interaction with the tip link. Changes in the MT conductance and Ca2+ permeability observed in the absence of Tmc1 mutants may stem from loss of interaction with protein partners in the transduction complex.

scholarly journals The Rho GTPase Cell Division Cycle 42 Regulates Stereocilia Development in Cochlear Hair Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Haibo Du ◽  
Hao Zhou ◽  
Yixiao Sun ◽  
Xiaoyan Zhai ◽  
Zhengjun Chen ◽  
...  
Keyword(s):  
Cell Division ◽  
Hair Cell ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Rho Gtpase ◽  
Cell Division Cycle ◽  
Pivotal Role ◽  
Apical Surface ◽  
Cochlear Hair Cells

Stereocilia are actin-based cell protrusions on the apical surface of inner ear hair cells, playing a pivotal role in hearing and balancing sensation. The development and maintenance of stereocilia is tightly regulated and deficits in this process usually lead to hearing or balancing disorders. The Rho GTPase cell division cycle 42 (CDC42) is a key regulator of the actin cytoskeleton. It has been reported to localize in the hair cell stereocilia and play important roles in stereocilia maintenance. In the present work, we utilized hair cell-specific Cdc42 knockout mice and CDC42 inhibitor ML141 to explore the role of CDC42 in stereocilia development. Our data show that stereocilia height and width as well as stereocilia resorption are affected in Cdc42-deficient cochlear hair cells when examined at postnatal day 8 (P8). Moreover, ML141 treatment leads to planar cell polarity (PCP) deficits in neonatal hair cells. We also show that overexpression of a constitutively active mutant CDC42 in cochlear hair cells leads to enhanced stereocilia developmental deficits. In conclusion, the present data suggest that CDC42 plays a pivotal role in regulating hair cell stereocilia development.

scholarly journals Essential Role of Sptan1 in Cochlear Hair Cell Morphology and Function Via Focal Adhesion Signaling

2021 ◽  
Author(s):  
Qingxiu Yao ◽  
Hui Wang ◽  
Hengchao Chen ◽  
Zhuangzhuang Li ◽  
Yumeng Jiang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Focal Adhesion ◽  
Hair Cells ◽  
Focal Adhesions ◽  
Organ Of Corti ◽  
Cochlear Hair Cell ◽  
Cuticular Plate ◽  
And Function

AbstractHearing loss is the most common human sensory deficit. Hearing relies on stereocilia, inserted into the cuticular plate of hair cells (HCs), where they play an important role in the perception of sound and its transmission. Although numerous genes have been associated with hearing loss, the function of many hair cell genes has yet to be elucidated. Herein, we focused on nonerythroid spectrin αII (SPTAN1), abundant in the cuticular plate, surrounding the rootlets of stereocilia and along the plasma membrane. Interestingly, mice with HC-specific Sptan1 knockout exhibited rapid deafness, abnormal formation of stereocilia and cuticular plates, and loss of HCs from middle and apical turns of the cochlea during early postnatal stages. Additionally, Sptan1 deficiency led to the decreased spreading of House Ear Institute-Organ of Corti 1 cells, and induced abnormal formation of focal adhesions and integrin signaling in mouse HCs. Altogether, our findings highlight SPTAN1 as a critical molecule for HC stereocilia morphology and auditory function via regulation of focal adhesion signaling.

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