{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T04:48:12Z","timestamp":1793681292216,"version":"4.5.1"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011825","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005879","name":"National Centre for Biological Sciences","doi-asserted-by":"publisher","award":["RTI4006"],"award-info":[{"award-number":["RTI4006"]}],"id":[{"id":"10.13039\/501100005879","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020172","name":"Royal National Institute for Deaf People","doi-asserted-by":"publisher","award":["G97"],"award-info":[{"award-number":["G97"]}],"id":[{"id":"10.13039\/501100020172","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"SERB","doi-asserted-by":"crossref","award":["CRG"],"award-info":[{"award-number":["CRG"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007296","name":"Infosys Foundation","doi-asserted-by":"publisher","award":["TIFR-Infosys Leading Edge Grant"],"award-info":[{"award-number":["TIFR-Infosys Leading Edge Grant"]}],"id":[{"id":"10.13039\/501100007296","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000893","name":"Simons Foundation","doi-asserted-by":"publisher","award":["Simons-Ashoka Early Career Fellowship"],"award-info":[{"award-number":["Simons-Ashoka Early Career Fellowship"]}],"id":[{"id":"10.13039\/100000893","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    In vertebrates, auditory information is transduced in the cochlea by mechanosensory hair cells (HC) through an eccentrically organised structure known as the hair bundle. This consists of a true cilium, known as the kinocilium, and modified microvilli, known as stereocilia. The hair bundle has a distinct structure with stereocilia organised in graded rows, with the longest abutting the kinocilium. The hair bundles of all HC are aligned to the tissue axis and are planar polarised. Important in the development and physiology of HC are protein bridges consisting of cadherin-23 (CDH23) and protocadherin-15 (PCDH15). These link the tips of stereocilia, where they play a role in mechanotransduction, and between the kinocilia and the stereocilia, where they are involved in development. Both\n                    <jats:italic>\n                      <jats:italic>Cdh23<\/jats:italic>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      <jats:italic>Pcdh15<\/jats:italic>\n                    <\/jats:italic>\n                    mutations result in defects in planar polarity; however, the mechanism through which this defect arises is unclear. Using a novel mutant for the\n                    <jats:italic>\n                      <jats:italic>Pcdh15-CD2<\/jats:italic>\n                    <\/jats:italic>\n                    isoform, we show that while the initial deflection of the kinocilium occurs, its peripheral migration to register with G\u03b1i is perturbed.\n                    <jats:italic>\n                      <jats:italic>Pcdh15-CD2<\/jats:italic>\n                    <\/jats:italic>\n                    genetically interacts with\n                    <jats:italic>\n                      <jats:italic>Gpsm2<\/jats:italic>\n                    <\/jats:italic>\n                    , perturbing vestibular function. We find that the earliest expression of PCDH15-CD2 is at the base of the kinocilia, and the defects in morphogenesis occur before the formation of kinocilial links. By re-introducing functional PCDH15-CD2, we show that polarity can be restored. Our data suggest that, in addition to its adhesive role, PCDH15-CD2 has an early role in intrinsic hair cell polarity through a mechanism independent of kinocilial links.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011825","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T18:23:57Z","timestamp":1755109437000},"page":"e1011825","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Role of Pcdh15 in the development of intrinsic polarity of inner ear hair cells"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6953-2924","authenticated-orcid":true,"given":"Raman","family":"Kaushik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-2528","authenticated-orcid":true,"given":"Shivangi","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-8212","authenticated-orcid":true,"given":"Anubhav","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0936-0194","authenticated-orcid":true,"given":"Fenil","family":"Ganatra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5885-4875","authenticated-orcid":true,"given":"Takaya","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1509-8747","authenticated-orcid":true,"given":"Hiroshi","family":"Kiyonari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3613-9456","authenticated-orcid":true,"given":"Raj K.","family":"Ladher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"pgen.1011825.ref001","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-genet-102108-134135","article-title":"Hearing loss: mechanisms revealed by genetics and cell biology","volume":"43","author":"AA Dror","year":"2009","journal-title":"Annu Rev Genet"},{"issue":"12","key":"pgen.1011825.ref002","doi-asserted-by":"crossref","DOI":"10.1242\/dev.162263","article-title":"Development of the cochlea","volume":"147","author":"EC Driver","year":"2020","journal-title":"Development"},{"key":"pgen.1011825.ref003","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev.cb.08.110192.001353","article-title":"Actin filaments, stereocilia, and hair cells: how cells count and measure","volume":"8","author":"LG Tilney","year":"1992","journal-title":"Annu Rev Cell Biol"},{"key":"pgen.1011825.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.1981.tb30854.x","article-title":"Directional sensitivity of individual vertebrate hair cells to controlled deflection of their hair bundles","volume":"374","author":"SL Shotwell","year":"1981","journal-title":"Ann N Y Acad Sci"},{"issue":"1","key":"pgen.1011825.ref005","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/0012-1606(86)90047-3","article-title":"Actin filaments, stereocilia, and hair cells of the bird cochlea. III. The development and differentiation of hair cells and stereocilia.","volume":"116","author":"LG Tilney","year":"1986","journal-title":"Dev Biol"},{"issue":"2","key":"pgen.1011825.ref006","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/cne.903500204","article-title":"Postnatal development of the hamster cochlea. II. Growth and differentiation of stereocilia bundles","volume":"350","author":"JA Kaltenbach","year":"1994","journal-title":"J Comp Neurol"},{"key":"pgen.1011825.ref007","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/0006-8993(96)00147-3","article-title":"Development of the auditory receptors of the rat: a SEM study","volume":"721","author":"A Zine","year":"1996","journal-title":"Brain Res"},{"key":"pgen.1011825.ref008","article-title":"Initiation and Formation of Stereocilia during the Development of Mouse Cochlear Hair Cells","volume":"2024","author":"SR Chakravarthy","journal-title":"bioRxiv"},{"issue":"1","key":"pgen.1011825.ref009","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.devcel.2013.09.011","article-title":"A molecular blueprint at the apical surface establishes planar asymmetry in cochlear hair cells","volume":"27","author":"B Tarchini","year":"2013","journal-title":"Dev Cell"},{"issue":"9","key":"pgen.1011825.ref010","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/ncb2819","article-title":"Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton","volume":"15","author":"J Ezan","year":"2013","journal-title":"Nat Cell Biol"},{"key":"pgen.1011825.ref011","doi-asserted-by":"crossref","first-page":"134373","DOI":"10.1016\/j.neulet.2019.134373","article-title":"New insights into regulation and function of planar polarity in the inner ear","volume":"709","author":"B Tarchini","year":"2019","journal-title":"Neurosci Lett"},{"issue":"1","key":"pgen.1011825.ref012","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a033266","article-title":"Development and Patterning of the Cochlea: From Convergent Extension to Planar Polarity","volume":"10","author":"M Montcouquiol","year":"2020","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"1","key":"pgen.1011825.ref013","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.devcel.2011.06.012","article-title":"Mitotic spindle orientation in asymmetric and symmetric cell divisions during animal development","volume":"21","author":"X Morin","year":"2011","journal-title":"Dev Cell"},{"key":"pgen.1011825.ref014","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00335-015-9614-7","article-title":"The GPSM2\/LGN GoLoco motifs are essential for hearing","volume":"27","author":"Y Bhonker","year":"2016","journal-title":"Mamm Genome"},{"key":"pgen.1011825.ref015","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.88186","article-title":"Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis","volume":"12","author":"A Jarysta","year":"2024","journal-title":"Elife"},{"issue":"10","key":"pgen.1011825.ref016","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/ng1644","article-title":"Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates","volume":"37","author":"AJ Ross","year":"2005","journal-title":"Nat Genet"},{"issue":"1","key":"pgen.1011825.ref017","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/ng.2007.54","article-title":"Ciliary proteins link basal body polarization to planar cell polarity regulation","volume":"40","author":"C Jones","year":"2008","journal-title":"Nat Genet"},{"issue":"3","key":"pgen.1011825.ref018","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1242\/dev.113696","article-title":"Ciliary proteins Bbs8 and Ift20 promote planar cell polarity in the cochlea","volume":"142","author":"HL May-Simera","year":"2015","journal-title":"Development"},{"issue":"16","key":"pgen.1011825.ref019","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1242\/dev.065961","article-title":"Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms","volume":"138","author":"CW Sipe","year":"2011","journal-title":"Development"},{"issue":"3","key":"pgen.1011825.ref020","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1093\/hmg\/ddq493","article-title":"Alstr\u00f6m Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity","volume":"20","author":"D Jagger","year":"2011","journal-title":"Hum Mol Genet"},{"issue":"12","key":"pgen.1011825.ref021","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a033142","article-title":"Hair-Bundle Links: Genetics as the Gateway to Function","volume":"9","author":"GP Richardson","year":"2019","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"2","key":"pgen.1011825.ref022","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s10162-005-0024-5","article-title":"Progression of inner ear pathology in Ames waltzer mice and the role of protocadherin 15 in hair cell development","volume":"7","author":"KS Pawlowski","year":"2006","journal-title":"J Assoc Res Otolaryngol"},{"issue":"8","key":"pgen.1011825.ref023","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1242\/dev.012922","article-title":"A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth","volume":"135","author":"G Lef\u00e8vre","year":"2008","journal-title":"Development"},{"issue":"1","key":"pgen.1011825.ref024","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1086\/321277","article-title":"Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F","volume":"69","author":"ZM Ahmed","year":"2001","journal-title":"Am J Hum Genet"},{"issue":"16","key":"pgen.1011825.ref025","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1093\/hmg\/10.16.1709","article-title":"Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F","volume":"10","author":"KN Alagramam","year":"2001","journal-title":"Hum Mol Genet"},{"issue":"1","key":"pgen.1011825.ref026","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/83837","article-title":"The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene","volume":"27","author":"KN Alagramam","year":"2001","journal-title":"Nat Genet"},{"issue":"26","key":"pgen.1011825.ref027","doi-asserted-by":"crossref","first-page":"7022","DOI":"10.1523\/JNEUROSCI.1163-06.2006","article-title":"The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15","volume":"26","author":"ZM Ahmed","year":"2006","journal-title":"J Neurosci"},{"issue":"8","key":"pgen.1011825.ref028","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1242\/dev.060061","article-title":"Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain","volume":"138","author":"SW Webb","year":"2011","journal-title":"Development"},{"issue":"33","key":"pgen.1011825.ref029","doi-asserted-by":"crossref","first-page":"8388","DOI":"10.1073\/pnas.1719861115","article-title":"FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia","volume":"115","author":"A Honda","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pgen.1011825.ref030","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/cne.20513","article-title":"Development and properties of stereociliary link types in hair cells of the mouse cochlea","volume":"485","author":"RJ Goodyear","year":"2005","journal-title":"J Comp Neurol"},{"issue":"7","key":"pgen.1011825.ref031","doi-asserted-by":"crossref","first-page":"107653","DOI":"10.1016\/j.celrep.2020.107653","article-title":"Pronuclear Microinjection during S-Phase Increases the Efficiency of CRISPR-Cas9-Assisted Knockin of Large DNA Donors in Mouse Zygotes","volume":"31","author":"T Abe","year":"2020","journal-title":"Cell Rep"},{"issue":"7","key":"pgen.1011825.ref032","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1093\/bioinformatics\/btu743","article-title":"CRISPRdirect: software for designing CRISPR\/Cas guide RNA with reduced off-target sites","volume":"31","author":"Y Naito","year":"2015","journal-title":"Bioinformatics"},{"issue":"2","key":"pgen.1011825.ref033","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1023\/A:1008868325009","article-title":"Maternally expressed PGK-Cre transgene as a tool for early and uniform activation of the Cre site-specific recombinase","volume":"7","author":"Y Lallemand","year":"1998","journal-title":"Transgenic Res"},{"issue":"1","key":"pgen.1011825.ref034","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41556-019-0436-9","article-title":"Endfoot regeneration restricts radial glial state and prevents translocation into the outer subventricular zone in early mammalian brain development","volume":"22","author":"I Fujita","year":"2020","journal-title":"Nat Cell Biol"},{"issue":"1","key":"pgen.1011825.ref035","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.neuron.2005.08.028","article-title":"Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors","volume":"48","author":"R Machold","year":"2005","journal-title":"Neuron"},{"issue":"3","key":"pgen.1011825.ref036","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.ymeth.2013.06.011","article-title":"From placode to labyrinth: culture of the chicken inner ear","volume":"66","author":"A Honda","year":"2014","journal-title":"Methods"},{"issue":"184","key":"pgen.1011825.ref037","doi-asserted-by":"crossref","DOI":"10.3791\/64172","article-title":"In Ovo and Ex Ovo Methods to Study Avian Inner Ear Development","author":"N Singh","year":"2022","journal-title":"J Vis Exp"},{"issue":"7","key":"pgen.1011825.ref038","doi-asserted-by":"crossref","first-page":"984","DOI":"10.15252\/emmm.201403976","article-title":"The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells","volume":"6","author":"E Pepermans","year":"2014","journal-title":"EMBO Mol Med"},{"issue":"18","key":"pgen.1011825.ref039","doi-asserted-by":"crossref","first-page":"7013","DOI":"10.1523\/JNEUROSCI.21-18-07013.2001","article-title":"FM1-43 dye behaves as a permeant blocker of the hair-cell mechanotransducer channel","volume":"21","author":"JE Gale","year":"2001","journal-title":"J Neurosci"},{"issue":"19","key":"pgen.1011825.ref040","article-title":"Dual regulation of planar polarization by secreted Wnts and Vangl2 in the developing mouse cochlea","volume":"147","author":"EH Najarro","year":"2020","journal-title":"Development"},{"issue":"52","key":"pgen.1011825.ref041","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1716522115","article-title":"Daple coordinates organ-wide and cell-intrinsic polarity to pattern inner-ear hair bundles","volume":"114","author":"K Siletti","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"23","key":"pgen.1011825.ref042","doi-asserted-by":"crossref","DOI":"10.1172\/JCI177700","article-title":"PCDH15 dual-AAV gene therapy for deafness and blindness in Usher syndrome type 1F models","volume":"134","author":"MV Ivanchenko","year":"2024","journal-title":"J Clin Invest"},{"issue":"2","key":"pgen.1011825.ref043","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/ar.20632","article-title":"Development of outer hair cells in Ames waltzer mice: mutation in protocadherin 15 affects development of cuticular plate and associated structures","volume":"291","author":"YS Kikkawa","year":"2008","journal-title":"Anat Rec (Hoboken)"},{"issue":"8","key":"pgen.1011825.ref044","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1242\/dev.089763","article-title":"Lis1 mediates planar polarity of auditory hair cells through regulation of microtubule organization","volume":"140","author":"CW Sipe","year":"2013","journal-title":"Development"},{"issue":"5","key":"pgen.1011825.ref045","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41556-020-0492-1","article-title":"Pac1\/LIS1 stabilizes an uninhibited conformation of dynein to coordinate its localization and activity","volume":"22","author":"MG Marzo","year":"2020","journal-title":"Nat Cell Biol"},{"issue":"16","key":"pgen.1011825.ref046","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1242\/dev.077511","article-title":"Regulation of dynein localization and centrosome positioning by Lis-1 and asunder during Drosophila spermatogenesis","volume":"139","author":"P Sitaram","year":"2012","journal-title":"Development"},{"issue":"1","key":"pgen.1011825.ref047","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.1038\/s41467-025-58557-0","article-title":"Junctional force patterning drives both positional order and planar polarity in the auditory epithelia","volume":"16","author":"A Prakash","year":"2025","journal-title":"Nat Commun"},{"key":"pgen.1011825.ref048","doi-asserted-by":"crossref","first-page":"14907","DOI":"10.1038\/ncomms14907","article-title":"Defective Gpsm2\/G\u03b1i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome","volume":"8","author":"SA Mauriac","year":"2017","journal-title":"Nat Commun"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1011825","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1011825","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T18:00:49Z","timestamp":1755799249000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1011825"}},"subtitle":[],"editor":[{"given":"Nandan","family":"Nerurkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":48,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1011825","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]}}}