Journal of Cell Science hndcie ntopae hntedfeto smitie,a maintained, is produced deflection the current when gating phases The two the deflections. in channel, declines positive then open’ MET during ‘pulls the effect, channel in to which, the 1983), attached Hudspeth, is and (Corey that spring bundle the in 2006). Hackney, cationic and nonselective Furness gated by Thus, mechanically review cell. (see a the channel is of channel hyperpolarization reduce in MET and resulting the channels ions, the of close flow row the shortest the towards direction arcells sensory hair in vertebrate links in cross transduction of mechanoelectrical role and composition The Commentary n Mg mechanoelectrical and K of the of means of by cell direction opening hair the the depolarizes in the row deflection tallest Displacement modulates channels; it. (MET) across bundle tall transduction to the short from of rows height forming in bundle, the increase single within that hair organization a precise individual a on also In have stereocilia bundle. cells the is the epithelia, actin of being there hair-cell side vertebrate one of exception cochlea, to all located the mammalian array kinocilium, the adult bundles, called longitudinal cilium, the hair a of sensory vertebrate with those most These filled the 1A). In (Fig. actually structures filaments. stereocilia of are stiff called which are are receptors ‘hairs’), and (the microvilli sensory protrusions modified apical cellular an of the have bundle mechanosensors These are system. acousticolateralis cells Hair Introduction the gates and 15, protocadherin impairment. and hearing 23 human cadherin to bundle relevant function optimal of structure, be maintains composed the might links, words: of about is they Key horizontal) available how measurements (or link, currently and lateral mechanical information tip links called the and the the link, summarizes biology of of Commentary link, molecular composition This type cross transduction. the and Another deafness, for of of deflected. of stiffness some is extracellular type and genetics of bundle nerve cohesion and one the causing the the transduction base, when that into mechanoelectrical cell from channel underlying thought research the transduction mechanisms by ions to is cellular connect of assisted It the allowing which release extracellular of been function. the fibres, Identification causes channels has nerve by brain. that sensory involved the together potential cation the to proteins receptor of connected sent a nonselective terminals be produces microvilli, the to This open onto signals transduction. actin-containing glutamate mechanoelectrical deflections neurotransmitter modified called excitatory process Stereociliary have are the a cells cell, these which links. the apex, their into protrusions, At cross environment cells. cellular hair called sensory specialized are balance) filaments of and hearing bundle line, (lateral systems a acousticolateralis of components key The Summary 10.1242/jcs.106120 doi: 1721–1731 126, ß Science Cell of Journal ( correspondence for *Author 2 1 Hackney M. Carole neigtruhteMTcanl.(te ain uha Na as such cations (Other channels. MET the through entering anctosfudaon h bundle the around found cations main colo ieSine n nttt o cec n ehooyi eiie el nvriy tfodhr,S55G UK 5BG, ST5 Staffordshire, University, Keele Medicine, UK in 2TN, Technology S10 and Yorkshire, Science South for Sheffield, Institute Bank, and Western Sciences Sheffield, Life of of University School Science, Biomedical of Department 03 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2013. h prtn ehns sacie oamcaia element mechanical a to ascribed is mechanism operating The 2+ a astruhteMTcanl u r o the not are but channels MET the through pass can cutcltrlssses ahrn2,Ltrllns ehneetia rndcin rtcdei 5 troii,Tplinks Tip Stereocilia, 15, Protocadherin transduction, Mechanoelectrical links, Lateral 23, Cadherin systems, Acousticolateralis [email protected] 1 n ai .Furness N. David and nvivo in ) )Dfetosi the in Deflections .) + n Ca and 2, * 2+ ions + rcs hti Ca is that process ake,18)adas oncigtebnl othe to bundle and the Furness connecting 1984; al., also et and (Pickles a 1985) rows along both between Hackney, stereocilia, 1984; and of al., rows horizontally row the et are connecting links (Pickles lateral links bundle The directed it 1985). the behind Hackney, tips of and located axis stereocilium Furness excitatory stereocilium shorter the longer the along neighbouring a of the comprises main the each link two with tip to connects are The there that links. stereocilia lateral but filament and types, tallest links varies different tip together filaments of categories, the these cells stereocilia of hair link distribution between the precise also The hold kinocilium. and that 1B–G) (Fig. filaments extracellular be motor. to considered adaptation not the is for myosin this candidate so a 2002), in not al., do et they (Kros XVa, adaptation it affect abolish candidates. also myosin are VIIa and 2004) myosin Cyr, in 2009), adaptation both defects and Frolenkov, Although Gillespie by slower which and review (see (Stepanyan 1c a for cells myosin hair is 2007) inner phase Holt, in cochlear motile found second and those in The (Stauffer are involved cells.) myosins generally unconventional are nonmuscle cells; and in muscles, processes in actin, instance with interact for that molecules cells, and are hair (Stepanyan (Myosins some myosin 2009). in unconventional Frolenkov, potentially, an or, XVa, 2006) (Ricci myosin al., itself requires et channel Beurg the 1998; of al., property et intrinsic an reflect might that udmna etr falhi ude stepeec of presence the is bundles hair all of feature fundamental A 2+ estv;tefrtpaei ai adaptation rapid a is phase first the sensitive; 1721 Journal of Cell Science ucin.Tebscfaue ftehi udeadlnsare links 1G. and Fig. bundle in respective summarized hair their and the 1A–F for Fig. of in suggestions features illustrated with basic The along studies, and functions. discussed ultrastructural links from tip be primarily the will of described features as anatomical links, main lateral the section, this In lateral and links tip links of function and Structure linkages the hearing. of in basis role molecular their provided the and have about also that information mutations will molecular animal further It their and links. human about tip some This indicate known on stereociliary 2005). primarily currently of concentrating al., is function composition, its what et and that and structure Sotomayor idea the linkages 2000; the discuss the al., will be also to article et is stiff too there (Kachar is it and spring indicate the might link, and between composition connection links tip and still the structure tip the of of are nature and role the channel there the as of such However, view links, lateral basic in together. be this to with likely stereocilia more uncertainties is links the lateral tension the holding releasing of function them, The relax 1). gate, (Box would channel deflections MET would the they opposing deflections on because depolarizing and tension that putting links thereby way tip them, a the stretch such by in that represented situated suggested is are been has spring It gating 1988). the al., et (Takumida kinocilium 1722 elcin ea h pigadalwtecanl ocoe iueaatdfo uns ta. 2010. al., et Furness from adapted Figure close. to channels the allow and spring the relax deflections oae tteed ftetplnswt eeteiec aorn h oe n,a hw ntefgr Buge l,20) h schematic K mechanically The which allow 2009). spring), to gating al., a inset) et as (Beurg the (represented Deflect link figure in stereocilia. tip the of red the row in on (S) in tension short shown the puts (depicted as to arrow) channel intermediate end, the the by lower the and (indicated (I), the open direction intermediate are favouring excitatory the pulls channels to the evidence MET (T) in recent the tall bundle that the with the is connect of links that channels links mechanotransduction tip the the the shows of below of opening illustration the ends underlying the mechanism at the for located model accepted widely mechanotransduction most of The model tip-link Simplified 1. Box ora fCl cec 2 (8) 126 Science Cell of Journal Deflection + link Tip n Ca and E hnesaelctdna n rohredo h link. the of end high-speed other the and 2006) or provided al., spring, one et gating near (Beurg studies a located Electrophysiological represent are to channels location MET ideal links. an other that in from possible distinct is absolutely In making not it is 2006), Thus, 1989). link identify. Hackney, tip al., tips to and the difficult tips (Furness et links the the cells tip at (Furness hair individual observed at adult link be still some links tip can in links of main multiple organs, one vestibular number As many to link. the tip individual diminishes have an progresses, identify and to stereocilia stereocilia, possible development always taller not of adjacent thus the is it tips to bundle them hair of the connecting stages filaments row upwards- early however, the During (the in 1984). filament development, stereocilia al., single et taller (Pickles a to behind shorter bundles, study connecting a hair link) and adult pointing spring, in gating link a the as identified tip microscopy act electron could scanning high-resolution that using bundle structures hair This specific the identify 1982). to in (Hudspeth, attempting could studies Hudspeth anatomical and stereocilia to led suggestions 1981) between from (Thurm, stems Thurm link spring by gating extracellular channel MET an the represent that idea The links Tip Ca h oe n ftetpln Bx1 u hstcnqei of is technique this but 1) (Box link tip the at thus of stereocilia, end shorter the lower of tips the the at located channels MET 2+ eeteesi ayhi ude,asnl i iki present is link tip single a bundles, hair many in Nevertheless 2+ ost lwi arw ne)addplrs h el Opposing cell. the depolarise and inset) (arrow, in flow to ions mgn Buge l,20)idct htteeae1o 2 or 1 are there that indicate 2009) al., et (Beurg imaging Ca K + 2+ ion Journal of Cell Science oncosi h aea ik ttetpo h als troii,sm fwihetn noteoelyn etra ebae(ep ta. 2011) al., et (Verpy membrane tectorial t overlaying of the region into Another extend 1992). which al., of et a some (Hackney with stereocilia, channels coincide tallest sodium may the that sensitivity of area amiloride tip an to the close shown, antibodies at of is with links region A region label lateral the contact to also the The appears Note is (right). link. also connectors links the mammals cross of in different end but the either connectors’ between ( at row. interrelationship patch a of dense within illustration a and schematic is rows adjacent which in of those each ( connecting within (arrowhead). stereocilia, stereocilia tall between region) and (contact short the connecting (arrow) filament ftelte tece h ebaea h troiir i,it tip, stereociliary the at membrane the although link, stretched tip the latter by the necessarily not if but deflections Furness this 1997) bundle al., by in 1992; et activated channels al., (Furness efficiently that be et suggests still (Hackney would modeling link location Kinematic tip 1996). the al., et from away nm 100 r once otle troii nteajcn o yfn iaet aldtplns(ros.( (arrows). links tip called filaments fine ( by site. row attachment adjacent upper the the in towards stereocilia bifurcate taller to connected are aasgetta h E hne slctdblwtetip, the below located The is was channel. channel MET MET which the that the effect suggest and localize data proteins an to amiloride-binding microscopy amiloride, to immunoelectron antibodies by using blocked by exploited is low channel the relatively channels, of MET amiloride-sensitive Although other with attempted. amiloride-binding compared was of an sensitivity channels presence microscopy, the the on electron detecting sites resolution on based higher approach using address To question location. precise this the indicate to resolution insufficient ( bundle. the of axis excitatory the along height in increase that bundles. rows well-defined hair form in stereocilia links The cross cochlea. rat and a stereocilia from of Organisation 1. Fig. 5 3 m ;B m; 5 0 m C nm; 600 5 0n;D nm; 50 5 0 m n F and E nm; 100 D rnmsineeto irsoy(E)o i ikfo unapgccla arcl,soigtefine the showing cell, hair cochlear guinea-pig a from link tip a of (TEM) microscopy electron Transmission ) E E fahrzna eto fagopo a arcl troii hwn iaetu aea ik (arrows) links lateral filamentous showing stereocilia hair-cell rat of group a of section horizontal a of TEM ) F E ftetrerw fgie-i troii,i hc h ifrn rs ik r iil lf)ada and (left) visible are links cross different the which in stereocilia, guinea-pig of rows three the of TEM ) 5 5 nm. 250 , ( A 50– cnigeeto irgah(E)o h troiir udeo ninrhi cell hair inner an of bundle stereociliary the of (SEM) micrograph electron Scanning ) n ot 03.Tetetwt h Ca the with Treatment 2003). Holt, and ocretywt h blt fhi el otasue(Ge transduce development to cells during hair appear of links ability tip the by with Identifiable operated concurrently link. is it tip that the evidence TMC2 physiological and and developmental (TMC1) channels, form 1 2011). to al., et protein known to (Kawashima are channel-like that MET available possible two transmembrane as are recently have suggested most proteins There that candidate channels, distribution. of no number antibodies and a the are localization been as As there exact location. their uncertain, such this determine remains in reagents channels are MET specific that the channels of MET identity on pull might ( o -aminophenoxy)ethane- ept h ifcliso oaiigteMTcanl hr is there channel, MET the localizing of difficulties the Despite C ls po i ik hs ik rqetyapa to appear frequently links These link. tip a of up Close ) N , N , N B 9 , troiir ik 1723 links Stereociliary E hwn htsotrstereocilia shorter that showing SEM ) N 9 ttaaei cd(BAPTA) acid -tetra-acetic 2+ ceaigaet2-bis- agent -chelating eino ‘top of region cl bars: Scale . approach op ´ le ´ oc Journal of Cell Science a eedo hsooia odtos o xml,its example, Ca For by the affected conditions. absence of be physiological or may architecture presence on presence its molecular depend but uncertain more The may any remains examining in only also bifurcated. links by all bifurcation not where are resolved addition, and In cells be species. (Furness sample fish observed may different hair been or This samples far vertebrate (roach) so 2006). all have fish Hackney, from links links tip teleost stereocilia tip unbifurcated The taller except in 2000). al., observed the et classes been Kachar of 1995; has two Furness, membrane bifurcation that and the Hackney so 1C; length to wound (Fig. its link helically connect The along of 2000). partway filaments Santi, composed bifurcates and is Tsuprun frequently it 2000; also al., that et but (Kachar strand strands single a we not 2008), length their al., to et regard 2008). 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MET the how of and mechanism the Determining link tip to 2012). the by of coupled al., supported composition idea molecular et an and the structure below), (Powers (see with models might spring consistent link gating be mathematical the the whereby well be link may itself tip idea not that the (Meyer of this structure model cytoskeleton fact, molecular distinct internal In proposed a the 1998). to actually al., channel et is MET the spring prompting the gating closed, connects the than link rather tip that open the idea channel destroying and MET that (Marquis al., the suggests et leaves spring study (Zhao transduction one gating of However, recovery the regeneration 1996). and their loss of and by links accompanied loss tip is of to Loss due 1997). 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(the close al., and approach et stereocilia) (Verpy shorter below tall insertion just of adjacent occurs tips connectors of Hackney, top the horizontal tops of and the category of Furness (another between regions stereocilia by connectors) particular review (top are (see connections there cells Nevertheless, hair species precise 2006). different of in The differs types 1985). links Hackney, and these other of and each appearance Furness to and 1984; location neighbours project al., nearest which et the 1E–G), links (Pickles attaching (Fig. lateral directions, stereocilia or all the links in of cross shafts horizontal the of between types various are There links Lateral h i ik pert nettruhtemmrn n might and membrane the through insert to appear links tip The h pe lcrndnepau per ohv regular a have to appears plaque electron-dense upper The 2+ ` idn n nidn.Frisac,myosin instance, For unbinding. and binding r ta. 2008). al., et vre Journal of Cell Science rpris hr r he ifrn udedmis(hoe al., et (Zhao domains the bundle to different three According functional are and there question. structural properties, different interesting with membranes another of disposition also is bundle 1986). al., et mammalian (Jeffries adult cells in as hair well vestibular as chicken 1999), as Richardson, such and vertebrates, (Goodyear non-mammalian adult in retained are iin(iPlae l,20;Aarmme l,2001b). al., et and Alagramam hearing 2001; al., human et affects Palma an (Di that al., syndrome, vision I condition et type (Kazmierczak Usher recessive in are links mutated autosomal tip are proteins form superfamily both to and 2007) interact have cadherin 2006) to (So al., proposed et (CDH23) (Ahmed been the (PCDH15) 23 15 Cadherin protocadherin of and links. 2004) tip members of components that knockouts and confirms mutations immunocytochemistry, from Evidence stimuli links links mechanical Tip the of transduce composition Molecular still possess not 2009). links, Frolenkov, do top and which (Stepanyan arrangement, tip mice, or staircase myosin-XVa-deficient the identifiable in al., connections lacking et as bundles (Hackney horizontal such stereocilia addition, shorter In with of 1992). tips the associated channels below MET connectors the be that to evidence remains some might is directly there more but transduction discovered, the be to Whether protein mature contribute 2003). the al., links candidate in in et present lateral (Goodyear but absent ones a cochlea, frequency) the is (low of example, apical a cells PTPRQ, hair frequency) for connectors in and (high basal shaft types; 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Ahmed, iodr fte r oto odvlpntpoel.Sm of Some properly. not develop do balance or and lost hearing are to contribution they potential if their disorders in lies links research mammalian of different avenue exploring. further worthwhile across a is is more, that because correlation few or possible a locations This from Hz species. frequencies 100,000 cochlear of range to different and wide hundred a in different detect distribution cells in and hair cells cochlear organs hair their by ear detected associated bundle, inner frequencies are different that in the the changes is with systematic role show to main might their composition if is stiffness example, For adaptation providing molecular understood. which well less in the even way as the and such important gating achieved. resolve mechanotransduction, of to mechanisms necessary of is aspects questions investigations. lower further the these require at found points Answering myosins insertion of tip-link role remains upper precise THMS, and the via and perhaps link, obtained tip be the to to coupled how is about channel the evidence Further combined methods. at microscopy immunocytochemical channel tip electron with the the using of identifying instance end directly for lower resolution, by the high confirmed at be be to to needs likely link, is which of channel, location MET The 2005). the with Petit, anomalies and cross-link (El-Amraoui and deafness in associated bundle mutations hair various produce (2) proteins in and these results tip transduction; which the of can fragments, failure regeneration of PCDH15 concomitant link and role tip CDH23 the (1) by clarifying inhibited that: be show towards sufficient they underlying way together have long evidence Taken link. a genetic (Kachar not go and spring may model biochemical gating this the the it 2000)], for that al., measured et that suggests of reflect which data to structural elasticity link, the as tip are [such there gating the as of indisputable, the not aspects as is unexplained channel link still MET tip of the the basis of of the spring function be gating to the likely Although is investigation. which further dimer, CDH23 the of untwisting nlsso os oesi ieyt otnet rn new bring linkages. to and bundle hair continue deafness but of to function human likely and links, structure of is the appreciated; models into studies fully cross insights mouse not genetic of still the the of analysis is in disorders combination of role such the a of maintenance have prevalence clearly the and deafness with establishment associated genes the ihapsil iucto stersl fCa of result the as bifurcation PCDH15, possible and CDH23 a of homodimers with conjoined two of consists he,Z . oder . izdi,S,Lgil . ea,P . er,M., Behra, K., P. Legan, A., Lagziel, S., Riazuddin, R., Goodyear, M., Z. Ahmed, Lefe A., Adato, References Charity. Grand the (now and RNID Loss) MRC, Hearing the Trust, on UK, Wellcome Action Research the Deafness Charity, Smith by Henry supported the been has research authors’ The Funding tutr n uatallso CH5 osnrmcdans FB3adtp 1 type and B. DFNB23 T. deafness Friedman, nonsyndromic syndrome. PCDH15: and Usher of S. alleles Riazuddin, mutant and M., structure Qasim, P., P. Belyantseva, nie,apoenascae ihtetasuto ope fsnoyhi el,is cells, hair sensory of complex transduction al. the et with S. protocadherin-15. Riazuddin, associated R., protein E. a Wilcox, S., antigen, K. Lilley, M., S. Burgess, ydoetp I,i ieyt eacmoeto neseeclaakelnsi the in links ankle interstereocilia of component a cells. be sensory to ear likely inner is C. IIA, Petit, type and syndrome A. El-Amraoui, D., rmtehmnprpcie h motneo i n lateral and tip of importance the perspective, human the From remain transduction to contribution their and links lateral The ve . epa,B,Mce,V,Mcasi . hreox . Weil, S., Chardenoux, N., Michalski, V., Michel, B., Delprat, G., `vre, u.Genet. Hum. .Neurosci. J. u.Ml Genet. Mol. Hum. 26 124 7022-7034. , 215-223. , 20) sei,tedfciepoeni Usher in protein defective the Usherin, (2005). 14 3921-3932. , 20) h tip-link The (2006). 2+ -dependent 20) Gene (2008). er,M,Ftilc,R,Nm .H n ic,A J. A. Ricci, and H. J. R. Nam, Fettiplace, R., and Fettiplace, M., M. Beurg, C. Hackney, G., M. Evans, M., Beurg, htahra . ilr . ibrig .J,Jbosi .M n Cosgrove, and M. M. Jablonski, J., W. Kimberling, C., Miller, G., Bhattacharya, eynsv,I . oe,E .adFida,T B. T. Friedman, and T. E. Boger, A., I. Belyantseva, ahao,M . oder .J,Rcado,G .adRsel .J. I. Russell, and P. G. Richardson, J., R. Goodyear, E., M. Bashtanov, uns,D . ake,C .adBns .J. D. Benos, and M. C. Hackney, N., D. 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Furness, rti eetv npol ihUhrssnrm yeIIa. type syndrome Usher’s with people in defective protein D. arcl ehntasue hnesuighg-pe acu imaging. calcium high-speed using channels mechanotransducer Neurosci. cell hair cochlear mammalian in cells. channel hair mechanotransducer calcium-selective conductance h iso ne a esr elseeclaadi seta o tics omto of formation staircase for essential is and stereocilia bundle. cell hair sensory ear the inner of tips the otiuin fsrcue estv oclimceainadsbiii treatment. subtilisin and chelation calcium to Physiol. sensitive J. structures ( of chick contributions of properties mechanical troii o niearie gis ea a hnesi lce yaioieand amiloride by blocked is channels Na+ renal against dihydrostreptomycin. raised antisera for stereocilia lcrnmcocpctomography. electron-microscopic J. A. opooyi raoyi utrso h os cochlea. mouse the of Science cultures Springer organotypic NY: in York, morphology New 95-153. pp. Popper), Inc. N. Media In A. Business cells. and and Fay hair R. vertebrate R. Eatock, of bundle stereociliary unapgcochlea. pig guinea members. superfamily cadherin 107 of subset a for mechanism Mu cells. sensory ear inner in bundle hair growing the Sci. of cohesion the underlie that for model mouse the waltzer, in 1D. disorganization type stereocilia syndrome cause Usher cadherin, K. of Noben-Trauth, are type and P. growth, K. bundle Steel, hair directly. B., interact for and required al. tips et products stereocilia P. gene the J. deafness at Hardelin, two located G., whirlin, Richardson, and P., XVa Legrain, I., Perfettini, aiitwdlrmouse. varitint-waddler cells. hair vertebrate in transduction mechanical hair sensory mammalian in mechanotransduction and links tip cells. al. affect P. 23 G. et cadherin Richardson, and P. J., C. F. Kros, W., Bernier, Marcotti, L., 1F. type Laer, syndrome Van Usher cause R., PCDH15 Genet. Knaus, protocadherin Mol. novel B., the in R. 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