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1.
Defects in myosin VIIa, the PDZ-domain-containing protein harmonin, cadherin 23, protocadherin 15, and the putative scaffolding protein sans, underlie five genetic forms of Usher syndrome type I (USH1), the most frequent cause of hereditary deafness-blindness in humans. Mice mutants defective for any of these proteins have a severe hearing impairment and display similar inner ear phenotypes characterized by the abnormal spreading of the sensory cells' stereocilia. These are highly specialized mechanoreceptive organelles derived from microvilli, that normally form a well-structured hair bundle at the apex of inner ear sensory cells. All the USH1 proteins, except sans, have been detected in the growing stereocilia. Moreover, biochemical studies have started to unravel the multiple direct molecular interactions between USH1 proteins. In particular, harmonin can bind to the other four USH1 proteins and to F-actin. Finally, cell biology studies have provided the first insights into the functions of these proteins, and revealed that cadherin 23, and probably protocadherin 15 also, are associated with transient lateral links that interconnect growing stereocilia. These connectors play a critical role in the differentiating hair bundle. 相似文献
2.
Myosin VIIa,harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle 总被引:14,自引:0,他引:14
Boëda B El-Amraoui A Bahloul A Goodyear R Daviet L Blanchard S Perfettini I Fath KR Shorte S Reiners J Houdusse A Legrain P Wolfrum U Richardson G Petit C 《The EMBO journal》2002,21(24):6689-6699
Deaf-blindness in three distinct genetic forms of Usher type I syndrome (USH1) is caused by defects in myosin VIIa, harmonin and cadherin 23. Despite being critical for hearing, the functions of these proteins in the inner ear remain elusive. Here we show that harmonin, a PDZ domain-containing protein, and cadherin 23 are both present in the growing stereocilia and that they bind to each other. Moreover, we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments, thereby identifying a novel anchorage mode of the cadherins to the actin cytoskeleton. Moreover, harmonin b interacts directly with myosin VIIa, and is absent from the disorganized hair bundles of myosin VIIa mutant mice, suggesting that myosin VIIa conveys harmonin b along the actin core of the developing stereocilia. We propose that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia. 相似文献
3.
Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development 总被引:5,自引:0,他引:5
Lagziel A Ahmed ZM Schultz JM Morell RJ Belyantseva IA Friedman TB 《Developmental biology》2005,280(2):295-306
Mutant alleles of the gene encoding cadherin 23 are associated with Usher syndrome type 1 (USH1D), isolated deafness (DFNB12) in humans, and deafness and circling behavior in waltzer (v) mice. Stereocilia of waltzer mice are disorganized and the kinocilia misplaced, indicating the importance of cadherin 23 for hair bundle development. Cadherin 23 was localized to developing stereocilia and proposed as a component of the tip link. We show that, during development of the inner ear, cadherin 23 is initially detected in centrosomes at E14.5, then along the length of emerging stereocilia, and later becomes concentrated at and subsequently disappears from the tops of stereocilia. In mature vestibular hair bundles, cadherin 23 is present along the kinocilium and in the region of stereocilia-kinocilium bonds, a pattern conserved in mammals, chicks, and frogs. Cadherin 23 is also present in Reissner's membrane (RM) throughout development. In homozygous v(6J) mice, a reported null allele, cadherin 23 was absent from stereocilia, but present in kinocilia, RM, and centrosomes. We reconciled these results by identifying two novel isoforms of Cdh23 unaffected in sequence and expression by the v(6J) allele. Our results suggest that Cdh23 participation in stereocilia links may be restricted to developing hair bundles. 相似文献
4.
Mosaic complementation demonstrates a regulatory role for myosin VIIa in actin dynamics of stereocilia 总被引:3,自引:0,他引:3
We have developed a bacterial artificial chromosome transgenesis approach that allowed the expression of myosin VIIa from the mouse X chromosome. We demonstrated the complementation of the Myo7a null mutant phenotype producing a fine mosaic of two types of sensory hair cells within inner ear epithelia of hemizygous transgenic females due to X inactivation. Direct comparisons between neighboring auditory hair cells that were different only with respect to myosin VIIa expression revealed that mutant stereocilia are significantly longer than those of their complemented counterparts. Myosin VIIa-deficient hair cells showed an abnormally persistent tip localization of whirlin, a protein directly linked to elongation of stereocilia, in stereocilia. Furthermore, myosin VIIa localized at the tips of all abnormally short stereocilia of mice deficient for either myosin XVa or whirlin. Our results strongly suggest that myosin VIIa regulates the establishment of a setpoint for stereocilium heights, and this novel role may influence their normal staircase-like arrangement within a bundle. 相似文献
5.
Cadherins and mechanotransduction by hair cells 总被引:1,自引:0,他引:1
Müller U 《Current opinion in cell biology》2008,20(5):557-566
Mechanotransduction, the conversion of a mechanical stimulus into an electrical signal is crucial for our ability to hear and to maintain balance. Recent findings indicate that two members of the cadherin superfamily are components of the mechanotransduction machinery in sensory hair cells of the vertebrate inner ear. These studies show that cadherin 23 (CDH23) and protocadherin 15 (PCDH15) form several of the extracellular filaments that connect the stereocilia and kinocilium of a hair cell into a bundle. One of these filaments is the tip link that has been proposed to gate the mechanotransduction channel in hair cells. The extracellular domains of CDH23 and PCDH15 differ in their structure from classical cadherins and their cytoplasmic domains bind to distinct effectors, suggesting that evolutionary pressures have shaped the two cadherins for their function in mechanotransduction. 相似文献
6.
Artur A. Indzhykulian Ruben Stepanyan Anastasiia Nelina Kateri J. Spinelli Zubair M. Ahmed Inna A. Belyantseva Thomas B. Friedman Peter G. Barr-Gillespie Gregory I. Frolenkov 《PLoS biology》2013,11(6)
Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism''s life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca2+-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery. 相似文献
7.
Rzadzinska AK Schneider ME Davies C Riordan GP Kachar B 《The Journal of cell biology》2004,164(6):887-897
We have previously shown that the seemingly static paracrystalline actin core of hair cell stereocilia undergoes continuous turnover. Here, we used the same approach of transfecting hair cells with actin-green fluorescent protein (GFP) and espin-GFP to characterize the turnover process. Actin and espin are incorporated at the paracrystal tip and flow rearwards at the same rate. The flux rates (approximately 0.002-0.04 actin subunits s(-1)) were proportional to the stereocilia length so that the entire staircase stereocilia bundle was turned over synchronously. Cytochalasin D caused stereocilia to shorten at rates matching paracrystal turnover. Myosins VI and VIIa were localized alongside the actin paracrystal, whereas myosin XVa was observed at the tips at levels proportional to stereocilia lengths. Electron microscopy analysis of the abnormally short stereocilia in the shaker 2 mice did not show the characteristic tip density. We argue that actin renewal in the paracrystal follows a treadmill mechanism, which, together with the myosins, dynamically shapes the functional architecture of the stereocilia bundle. 相似文献
8.
Giacomello M De Mario A Primerano S Brini M Carafoli E 《The international journal of biochemistry & cell biology》2012,44(5):679-683
Hearing relies on the ability of the inner ear to convert sound waves into electrical signals. The main actors in this process are hair cells. Their stereocilia contain a number of specific proteins and a scaffold of actin molecules. They are organized in bundles by tip-link filaments composed of cadherin 23 and protocadherin 15. The bundle is deflected by sound waves leading to the opening of mechano-transduction channels and to the influx of K(+) and Ca(2+) into the stereocilia. Cadherin 23 and the plasma membrane calcium ATPase isoform 2 (PMCA2) are defective in human and murine cases of deafness. While the involvement of cadherin 23 in deafness/hearing could be expected due to its structural role in the tip-links, that of PMCA2 has been discovered only recently. This review will summarize the structural and functional characteristics of hair cells, focusing on the proteins whose mutations may lead to a deafness phenotype. 相似文献
9.
Rzadzinska A Schneider M Noben-Trauth K Bartles JR Kachar B 《Cell motility and the cytoskeleton》2005,62(3):157-165
Hearing and balance depend on microvilli-like actin-based projections of sensory hair cells called stereocilia. Their sensitivity to mechanical displacements on the nanometer scale requires a highly organized hair bundle in which the physical dimension of each stereocilium is tightly controlled. The length and diameter of each stereocilium are established during hair bundle maturation and maintained by life-long continuing dynamic regulation. Here, we studied the role of the actin-bundling protein Espin in stereociliary growth by examining the hair cell stereocilia of Espin-deficient jerker mice (Espn(je)), and the effects of transiently overexpressing Espin in the neuroepithelial cells of the organ of Corti cultures. Using fluorescence scanning confocal and electron microscopy, we found that a lack of Espin results in inhibition of stereociliary growth followed by progressive degeneration of the hair bundle. In contrast, overexpression of Espin induced lengthening of stereocilia and microvilli that mirrored the elongation of the actin filament bundle at their core. Interestingly, Espin deficiency also appeared to influence the localization of Myosin XVa, an unconventional myosin that is normally present at the stereocilia tip at levels proportional to stereocilia length. These results indicate that Espin is important for the growth and maintenance of the actin-based protrusions of inner ear neuroepithelial cells. 相似文献
10.
Abhishek Kumar Mingxing Ouyang Koen Van den Dries Ewan James McGhee Keiichiro Tanaka Marie D. Anderson Alexander Groisman Benjamin T. Goult Kurt I. Anderson Martin A. Schwartz 《The Journal of cell biology》2016,214(2):231-244
The precise architecture of hair bundles, the arrays of mechanosensitive microvilli-like stereocilia crowning the auditory hair cells, is essential to hearing. Myosin IIIa, defective in the late-onset deafness form DFNB30, has been proposed to transport espin-1 to the tips of stereocilia, thereby promoting their elongation. We show that Myo3a−/−Myo3b−/− mice lacking myosin IIIa and myosin IIIb are profoundly deaf, whereas Myo3a-cKO Myo3b−/− mice lacking myosin IIIb and losing myosin IIIa postnatally have normal hearing. Myo3a−/−Myo3b−/− cochlear hair bundles display robust mechanoelectrical transduction currents with normal kinetics but show severe embryonic abnormalities whose features rapidly change. These include abnormally tall and numerous microvilli or stereocilia, ungraded stereocilia bundles, and bundle rounding and closure. Surprisingly, espin-1 is properly targeted to Myo3a−/−Myo3b−/− stereocilia tips. Our results uncover the critical role that class III myosins play redundantly in hair-bundle morphogenesis; they unexpectedly limit the elongation of stereocilia and of subsequently regressing microvilli, thus contributing to the early hair bundle shaping. 相似文献
11.
Dakshnamurthy Selvakumar Marian J. Drescher Dennis G. Drescher 《The Journal of biological chemistry》2013,288(10):7215-7229
12.
13.
Cadherin 23 is a component of the transient lateral links in the developing hair bundles of cochlear sensory cells 总被引:6,自引:0,他引:6
Michel V Goodyear RJ Weil D Marcotti W Perfettini I Wolfrum U Kros CJ Richardson GP Petit C 《Developmental biology》2005,280(2):281-294
Cadherin 23 is required for normal development of the sensory hair bundle, and recent evidence suggests it is a component of the tip links, filamentous structures thought to gate the hair cells' mechano-electrical transducer channels. Antibodies against unique peptide epitopes were used to study the properties of cadherin 23 and its spatio-temporal expression patterns in developing cochlear hair cells. In the rat, intra- and extracellular domain epitopes are readily detected in the developing hair bundle between E18 and P5, and become progressively restricted to the distal tip of the hair bundle. From P13 onwards, these epitopes are no longer detected in hair bundles, but immunoreactivity is observed in the apical, vesicle-rich, pericuticular region of the hair cell. In the P2-P3 mouse cochlea, immunogold labeling reveals cadherin 23 is associated with kinocilial links and transient lateral links located between and within stereociliary rows. At this stage, the cadherin 23 ectodomain epitope remains on the hair bundle following BAPTA or La(3+) treatment, but is lost following exposure to the protease subtilisin. In contrast, mechano-electrical transduction is abolished by BAPTA but unaffected by subtilisin. These results suggest cadherin 23 is associated with transient lateral links that have properties distinct from those of the tip-link. 相似文献
14.
Iman Sahly Eric Dufour Cataldo Schietroma Vincent Michel Amel Bahloul Isabelle Perfettini Elise Pepermans Amrit Estivalet Diane Carette Asadollah Aghaie Inga Ebermann Andrea Lelli Maria Iribarne Jean-Pierre Hardelin Dominique Weil José-Alain Sahel Aziz El-Amraoui Christine Petit 《The Journal of cell biology》2012,199(2):381-399
The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins—myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans—do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner–outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients. 相似文献
15.
In search of the hair-cell gating spring elastic properties of ankyrin and cadherin repeats 总被引:9,自引:0,他引:9
Mechanotransduction in vertebrate hair cells involves a biophysically defined elastic element (the "gating spring") that pulls on the transduction channels. The tip link, a fine filament made of cadherin 23 linking adjacent stereocilia in hair-cell bundles, has been suggested to be the gating spring. However, TRP channels that mediate mechanotransduction in Drosophila, zebrafish, and mice often have cytoplasmic domains containing a large number of ankyrin repeats that are also candidates for the gating spring. We have explored the elastic properties of cadherin and ankyrin repeats through molecular dynamics simulations using crystallographic structures of proteins with one cadherin repeat or 4 and 12 ankyrin repeats, and using models of 17 and 24 ankyrin repeats. The extension and stiffness of large ankyrin-repeat structures were found to match those predicted by the gating-spring model. Our results suggest that ankyrin repeats of TRPA1 and TRPN1 channels serve as the gating spring for mechanotransduction. 相似文献
16.
Lin Wu Lifeng Pan Chuchu Zhang Mingjie Zhang 《The Journal of biological chemistry》2012,287(40):33460-33471
Stereocilia tip links of inner ear hair cells are subjected to constant stretching during hair-bundle deflection, and accordingly are well designed to prevent from being broken by mechanical tensions. The roots of tip links, which couple tip links with the cytoskeleton, supposedly play important roles in withstanding large forces under stimulated conditions. The upper root of the tip link is mainly formed by the cytoplasmic tail of cadherin23 and its actin-anchoring protein harmonin. However, the detailed organization mode of the two proteins that gives rise to a strong upper root remains unclear. Here we show that the exon68-encoded peptide of cadherin23 can either interact with the N-terminal domain (NTD) of harmonin or form a homodimer. We demonstrate that the three harmonin binding sites of cadherin23, namely the NTD-binding motif, the exon68 peptide, and the C-terminal PDZ binding motif, do not synergize with each other in binding to harmonin, instead they facilitate formation of polymeric cadherin23/harmonin complexes. The exon68 peptide can promote the cadherin23/harmonin polymer formation via either binding to harmonin NTD or self-dimerization. We propose that the polymeric cadherin23/harmonin complex formed beneath the upper tip link membranes may serve as part of the stable rootlet structure for anchoring the tip links of stereocilia. 相似文献
17.
Glen M. Watson Lankhanh Pham Erin M. Graugnard Patricia Mire 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2008,194(9):811-820
We investigated hair bundle mechanoreceptors in sea anemones for a homolog of cadherin 23. A candidate sequence was identified from the database for Nematostella vectensis that has a shared lineage with vertebrate cadherin 23s. This cadherin 23-like protein comprises 6,074 residues. It is an integral protein that features three transmembrane alpha-helices and a large extracellular loop with 44 contiguous, cadherin (CAD) domains. In the second half of the polypeptide, the CAD domains occur in a quadruple repeat pattern. Members of the same repeat group (i.e., CAD 18, 22, 26, and so on) share nearly identical amino acid sequences. An affinity-purified antibody was generated to a peptide from the C-terminus of the cadherin 23-like polypeptide. The peptide is expected to lie on the exoplasmic side of the plasma membrane. In LM, the immunolabel produced punctate fluorescence in hair bundles. In TEM, immunogold particles were observed medially and distally on stereocilia of hair bundles. Dilute solutions of the antibody disrupted vibration sensitivity in anemones. We conclude that the cadherin 23-like polypeptide likely contributes to the mechanotransduction apparatus of hair bundle mechanoreceptors of anemones. 相似文献
18.
Neeliyath A. Ramakrishnan Marian J. Drescher Roberto L. Barretto Kirk W. Beisel James S. Hatfield Dennis G. Drescher 《The Journal of biological chemistry》2009,284(5):3227-3238
The cytoplasmic amino terminus of HCN1, the primary full-length HCN isoform
expressed in trout saccular hair cells, was found by yeast two-hybrid
protocols to bind the cytoplasmic carboxyl-terminal domain of a protocadherin
15a-like protein. HCN1 was immunolocalized to discrete sites on saccular hair
cell stereocilia, consistent with gradated distribution expected for tip link
sites of protocadherin 15a. HCN1 message was also detected in cDNA libraries
of rat cochlear inner and outer hair cells, and HCN1 protein was
immunolocalized to cochlear hair cell stereocilia. As predicted by the trout
hair cell model, the amino terminus of rat organ of Corti HCN1 was found by
yeast two-hybrid analysis to bind the carboxyl terminus of protocadherin 15
CD3, a tip link protein implicated in mechanosensory transduction. Specific
binding between HCN1 and protocadherin 15 CD3 was confirmed with pull-down
assays and surface plasmon resonance analysis, both predicting dependence on
Ca2+. In the presence of calcium chelators, binding between HCN1
and protocadherin 15 CD3 was characterized by a KD = 2.39
× 10-7 m. Ca2+ at 26.5-68.0
μm promoted binding, with KD = 5.26 ×
10-8 m (at 61 μm Ca2+). Binding
by deletion mutants of protocadherin 15 CD3 pointed to amino acids 158-179
(GenBank™ accession number ), with homology to the comparable
region in trout hair cell protocadherin 15a-like protein, as necessary for
binding to HCN1. Amino terminus binding of HCN1 to HCN1, hypothesized to
underlie HCN1 channel formation, was also found to be
Ca2+-dependent, although the binding was skewed toward a lower
effective maximum [Ca2+] than for the HCN1 interaction with
protocadherin 15 CD3. Competition may therefore exist in vivo between
the two binding sites for HCN1, with binding of HCN1 to protocadherin 15 CD3
favored between 26.5 and 68 μ XP_238200m Ca2+. Taken together,
the evidence supports a role for HCN1 in mechanosensory transduction of inner
ear hair cells.HCN12 is the
primary full-length HCN isoform underlying Ih
(hyperpolarization-activated, cyclic nucleotide-gated, nonselective cation
channel current) in a model hair cell preparation from the trout sacccule
(1). cAMP-gated
Ih, possibly in addition to the
mechanosensory-transduction current, sets the membrane potential for a
subpopulation of saccular hair cells
(2,
3). The membrane potential in
the saccular hair cell subpopulation is sufficiently depolarized to activate
voltage-gated calcium channels, permitting influx of calcium and secretion of
hair cell transmitter (2).
Given that saccular hair cells expressing IK1 in addition
to Ih are more hyperpolarized, not supporting activation
of the voltage-gated calcium channels, we predicted that spontaneous release
of transmitter from the subpopulation of hair cells would constitute hair
cell-generated spontaneous activity for the saccule
(1). However, little has been
previously reported on the morphological localization of the HCN1 isoform in
hair cells or possible links to structural proteins that mechanistically would
localize HCN1 in hair cells (for preliminary report, see Ref.
4). In general, little is known
about protein-protein interactions for the HCN isoforms that would modulate
Ih and/or the associated instantaneous current
(5).Protocadherin 15 is a proposed tip link protein involved in connecting
shorter stereocilia to adjacent taller stereocilia in the stereociliary array
of inner ear hair cells, facilitating the opening of the mechanosensory
transduction channel in response to auditory and vestibular stimuli. The
active tip link protein in Danio rerio is protocadherin 15a
(6), characterized by splice
variants in its carboxyl terminus. In the mammal, protocadherin 15 CD3 is
hypothesized to be a tip link protein at insertion sites in the tips of the
shorter stereocilia of the stereociliary array
(7,
8). 相似文献
19.
Zampini V Rüttiger L Johnson SL Franz C Furness DN Waldhaus J Xiong H Hackney CM Holley MC Offenhauser N Di Fiore PP Knipper M Masetto S Marcotti W 《PLoS biology》2011,9(4):e1001048
Hair cells of the mammalian cochlea are specialized for the dynamic coding of sound stimuli. The transduction of sound waves into electrical signals depends upon mechanosensitive hair bundles that project from the cell's apical surface. Each stereocilium within a hair bundle is composed of uniformly polarized and tightly packed actin filaments. Several stereociliary proteins have been shown to be associated with hair bundle development and function and are known to cause deafness in mice and humans when mutated. The growth of the stereociliar actin core is dynamically regulated at the actin filament barbed ends in the stereociliary tip. We show that Eps8, a protein with actin binding, bundling, and barbed-end capping activities in other systems, is a novel component of the hair bundle. Eps8 is localized predominantly at the tip of the stereocilia and is essential for their normal elongation and function. Moreover, we have found that Eps8 knockout mice are profoundly deaf and that IHCs, but not OHCs, fail to mature into fully functional sensory receptors. We propose that Eps8 directly regulates stereocilia growth in hair cells and also plays a crucial role in the physiological maturation of mammalian cochlear IHCs. Together, our results indicate that Eps8 is critical in coordinating the development and functionality of mammalian auditory hair cells. 相似文献
20.
R.K. Duncan J. C. Saunders 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2000,186(11):1095-1106
Inner ear hair cells exhibit many pathologies following exposure to intense sound, and the hair bundle is a major site of damage. This paper measures in vitro hair bundle motion on chick cochlear hair cells after intense in vitro and in vivo stimulation to explore the nature of hair bundle injury. Hair bundle stiffness, as well as relative and asymmetric motion of individual stereocilia, is controlled largely by the extracellular tip links, and a change in hair bundle motion was used to assess tip-link destruction following overstimulation. Intense in vitro stimulation caused a loss in stiffness that fully recovered within 10 min post-exposure. Relative and asymmetric stereocilia motion, however, were unchanged following the exposure, implying that tip links remained intact while the core or rootlet of the stereocilia were damaged and subsequently repaired. Intense and prolonged in vivo sound exposures produced stereocilia movements, measured in vitro, that were indicative of damage to stereocilia and tip links. Finally, the relative susceptibility of hair bundles to overstimulation was addressed by comparing stiffness loss with morphological features in the hair bundles. The loss of stiffness significantly increased as the amount of curvature in the hair bundle contour increased. 相似文献