scholarly journals Zebrafish Models for the Mechanosensory Hair Cell Dysfunction in Usher Syndrome 3 Reveal That Clarin-1 Is an Essential Hair Bundle Protein

2015 ◽  
Vol 35 (28) ◽  
pp. 10188-10201 ◽  
Author(s):  
S. R. Gopal ◽  
D. H.- C. Chen ◽  
S.-W. Chou ◽  
J. Zang ◽  
S. C. F. Neuhauss ◽  
...  
2019 ◽  
Vol 116 (22) ◽  
pp. 11000-11009 ◽  
Author(s):  
Suhasini R. Gopal ◽  
Yvonne T. Lee ◽  
Ruben Stepanyan ◽  
Brian M. McDermott ◽  
Kumar N. Alagramam

The pathogenic variant c.144T>G (p.N48K) in the clarin1 gene (CLRN1) results in progressive loss of vision and hearing in Usher syndrome IIIA (USH3A) patients. CLRN1 is predicted to be an essential protein in hair bundles, the mechanosensory structure of hair cells critical for hearing and balance. When expressed in animal models, CLRN1 localizes to the hair bundle, whereas glycosylation-deficient CLRN1N48K aggregates in the endoplasmic reticulum, with only a fraction reaching the bundle. We hypothesized that the small amount of CLRN1N48K that reaches the hair bundle does so via an unconventional secretory pathway and that activation of this pathway could be therapeutic. Using genetic and pharmacological approaches, we find that clarin1 knockout (clrn1KO/KO) zebrafish that express the CLRN1c.144T>G pathogenic variant display progressive hair cell dysfunction, and that CLRN1N48K is trafficked to the hair bundle via the GRASP55 cargo-dependent unconventional secretory pathway (GCUSP). On expression of GRASP55 mRNA, or on exposure to the drug artemisinin (which activates GCUSP), the localization of CLRN1N48K to the hair bundles was enhanced. Artemisinin treatment also effectively restored hair cell mechanotransduction and attenuated progressive hair cell dysfunction in clrn1KO/KO larvae that express CLRN1c.144T>G, highlighting the potential of artemisinin to prevent sensory loss in CLRN1c.144T>G patients.


2007 ◽  
Vol 93 (11) ◽  
pp. 4053-4067 ◽  
Author(s):  
Jean-Yves Tinevez ◽  
Frank Jülicher ◽  
Pascal Martin
Keyword(s):  

Development ◽  
1998 ◽  
Vol 125 (4) ◽  
pp. 557-566 ◽  
Author(s):  
T. Self ◽  
M. Mahony ◽  
J. Fleming ◽  
J. Walsh ◽  
S.D. Brown ◽  
...  

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.


1994 ◽  
Vol 71 (2) ◽  
pp. 666-684 ◽  
Author(s):  
R. A. Baird

1. Hair cells in whole-mount in vitro preparations of the utricular macula of the bullfrog (Rana catesbeiana) were selected according to their macular location and hair bundle morphology. The voltage responses of selected hair cells to intracellular current steps and sinusoids in the frequency range of 0.5-200 Hz were studied with conventional intracellular recordings. 2. The utricular macula is divided into medial and lateral parts by the striola, a 75- to 100-microns zone that runs for nearly the entire length of the sensory macula near its lateral border. The striola is distinguished from flanking extrastriolar regions by the elevated height of its apical surface and the wider spacing of its hair cells. A line dividing hair cells of opposing polarities, located near the lateral border of the striola, separates it into medial and lateral parts. On average, the striola consists of five to seven medial and two to three lateral rows of hair cells. 3. Utricular hair cells were classified into four types on the basis of hair bundle morphology. Type B cells, the predominant hair cell type in the utricular macula, are small cells with short sterocilia and kinocilia 2-6 times as long as their longest stereocilia. These hair cells were found throughout the extrastriola and, more rarely, in the striolar region. Three other hair cell types were restricted to the striolar region. Type C cells, found primarily in the outer striolar rows, resemble enlarged versions of Type B hair cells. Type F cells have kinocilia approximately equal in length to their longest stereocilia and are restricted to the middle striolar rows. Type E cells, found only in the innermost striolar rows, have short kinocilia with prominent kinociliary bulbs. 4. The resting potential of 99 hair cells was -58.0 +/- 7.6 (SD) mV and did not vary significantly for hair cells in differing macular locations or with differing hair bundle morphology. The RN of hair cells, measured from the voltage response to current steps, varied from 200 to > 2,000 M omega and was not well correlated with cell size. On average, Type B cells had the highest RN, followed by Type F, Type E, and Type C cells. When normalized to their surface area, the membrane resistance of hair cells ranged from < 1,000 to > 10,000 k omega.cm2. The input capacitance of hair cells ranged from < 3 to > 15 pA, corresponding on average to a membrane capacitance of 0.8 +/- 0.2 pA/cm2.(ABSTRACT TRUNCATED AT 400 WORDS)


PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e23729 ◽  
Author(s):  
Li-Dong Zhao ◽  
Wei-Wei Guo ◽  
Chang Lin ◽  
Li-Xian Li ◽  
Jian-He Sun ◽  
...  

2019 ◽  
Author(s):  
Francesco Gianoli ◽  
Thomas Risler ◽  
Andrei S. Kozlov

ABSTRACTHearing relies on the conversion of mechanical stimuli into electrical signals. In vertebrates, this process of mechano-electrical transduction (MET) is performed by specialized receptors of the inner ear, the hair cells. Each hair cell is crowned by a hair bundle, a cluster of microvilli that pivot in response to sound vibrations, causing the opening and closing of mechanosensitive ion channels. Mechanical forces are projected onto the channels by molecular springs called tip links. Each tip link is thought to connect to a small number of MET channels that gate cooperatively and operate as a single transduction unit. Pushing the hair bundle in the excitatory direction opens the channels, after which they rapidly reclose in a process called fast adaptation. It has been experimentally observed that the hair cell’s biophysical properties mature gradually during postnatal development: the maximal transduction current increases, sensitivity sharpens, transduction occurs at smaller hair-bundle displacements, and adaptation becomes faster. Similar observations have been reported during tip-link regeneration after acoustic damage. Moreover, when measured at intermediate developmental stages, the kinetics of fast adaptation varies in a given cell depending on the magnitude of the imposed displacement. The mechanisms underlying these seemingly disparate observations have so far remained elusive. Here, we show that these phenomena can all be explained by the progressive addition of MET channels of constant properties, which populate the hair bundle first as isolated entities, then progressively as clusters of more sensitive, cooperative MET channels. As the proposed mechanism relies on the difference in biophysical properties between isolated and clustered channels, this work highlights the importance of cooperative interactions between mechanosensitive ion channels for hearing.SIGNIFICANCEHair cells are the sensory receptors of the inner ear that convert mechanical stimuli into electrical signals transmitted to the brain. Sensitivity to mechanical stimuli and the kinetics of mechanotransduction currents change during hair-cell development. The same trend, albeit on a shorter timescale, is also observed during hair-cell recovery from acoustic trauma. Furthermore, the current kinetics in a given hair cell depends on the stimulus magnitude, and the degree of that dependence varies with development. These phenomena have so far remained unexplained. Here, we show that they can all be reproduced using a single unifying mechanism: the progressive formation of channel pairs, in which individual channels interact through the lipid bilayer and gate cooperatively.


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