{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:35:19Z","timestamp":1791959719765,"version":"4.3.4"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The National Institute of Health grant","award":["EY026614"],"award-info":[{"award-number":["EY026614"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Haplo-insufficiency of the <jats:italic>GATA3<\/jats:italic> gene causes hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome. Previous studies have shown that <jats:italic>Gata3<\/jats:italic> is required for the development of the prosensory domain and spiral ganglion neurons (SGNs) of the mouse cochlea during embryogenesis. However, its role in supporting cells (SCs) after cell fate specification is largely unknown. In this study, we used tamoxifen-inducible <jats:italic>Sox2<\/jats:italic><jats:sup><jats:italic>CreERT2<\/jats:italic><\/jats:sup> mice to delete <jats:italic>Gata3<\/jats:italic> in SCs of the neonatal mouse cochlea and showed that loss of <jats:italic>Gata3<\/jats:italic> resulted in the proliferation of SCs, including the inner pillar cells (IPCs), inner border cells (IBCs), and lateral greater epithelium ridge (GER). In addition, loss of <jats:italic>Gata3<\/jats:italic> resulted in the down-regulation of p27<jats:sup>kip1<\/jats:sup>, a cell cycle inhibitor, in the SCs of <jats:italic>Gata3-<\/jats:italic>CKO neonatal cochleae. Chromatin immunoprecipitation analysis revealed that GATA3 directly binds to <jats:italic>p27<\/jats:italic><jats:sup><jats:italic>kip1<\/jats:italic><\/jats:sup> promoter and could maintain the quiescent state of cochlear SCs by regulating <jats:italic>p27<\/jats:italic><jats:sup><jats:italic>kip1<\/jats:italic><\/jats:sup> expression. Furthermore, RNA-seq analysis revealed that loss of <jats:italic>Gata3<\/jats:italic> function resulted in the change in the expression of genes essential for the development and function of cochlear SCs, including <jats:italic>Tectb<\/jats:italic>, <jats:italic>Cyp26b1<\/jats:italic>, <jats:italic>Slitrk6<\/jats:italic>, <jats:italic>Ano1<\/jats:italic>, and <jats:italic>Aqp4<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/s41598-021-95427-3","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T10:04:26Z","timestamp":1628071466000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["GATA3 maintains the quiescent state of cochlear supporting cells by regulating p27kip1"],"prefix":"10.1038","volume":"11","author":[{"given":"Jiadong","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongliang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhui","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luming","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"95427_CR1","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.immuni.2007.04.018","volume":"27","author":"TC Fang","year":"2007","unstructured":"Fang, T. C. et al. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27, 100\u2013110. https:\/\/doi.org\/10.1016\/j.immuni.2007.04.018 (2007).","journal-title":"Immunity"},{"key":"95427_CR2","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/nri2476","volume":"9","author":"IC Ho","year":"2009","unstructured":"Ho, I. C., Tai, T. S. & Pai, S. Y. GATA3 and the T-cell lineage: Essential functions before and after T-helper-2-cell differentiation. Nat. Rev. Immunol. 9, 125\u2013135. https:\/\/doi.org\/10.1038\/nri2476 (2009).","journal-title":"Nat. Rev. Immunol."},{"key":"95427_CR3","doi-asserted-by":"publisher","first-page":"4503","DOI":"10.1172\/JCI57456","volume":"121","author":"EA Wohlfert","year":"2011","unstructured":"Wohlfert, E. A. et al. GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J. Clin. Invest. 121, 4503\u20134515. https:\/\/doi.org\/10.1172\/JCI57456 (2011).","journal-title":"J. Clin. Invest."},{"key":"95427_CR4","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1172\/JCI42021","volume":"120","author":"IV Grigorieva","year":"2010","unstructured":"Grigorieva, I. V. et al. Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2. J. Clin. Invest. 120, 2144\u20132155. https:\/\/doi.org\/10.1172\/JCI42021 (2010).","journal-title":"J. Clin. Invest."},{"key":"95427_CR5","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.mce.2015.04.018","volume":"411","author":"SI Han","year":"2015","unstructured":"Han, S. I., Tsunekage, Y. & Kataoka, K. Gata3 cooperates with Gcm2 and MafB to activate parathyroid hormone gene expression by interacting with SP1. Mol. Cell. Endocrinol. 411, 113\u2013120. https:\/\/doi.org\/10.1016\/j.mce.2015.04.018 (2015).","journal-title":"Mol. Cell. Endocrinol."},{"key":"95427_CR6","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1681\/ASN.2018111143","volume":"30","author":"IV Grigorieva","year":"2019","unstructured":"Grigorieva, I. V. et al. A novel role for GATA3 in mesangial cells in glomerular development and injury. J. Am. Soc. Nephrol. 30, 1641\u20131658. https:\/\/doi.org\/10.1681\/ASN.2018111143 (2019).","journal-title":"J. Am. Soc. Nephrol."},{"key":"95427_CR7","doi-asserted-by":"publisher","first-page":"e1000316","DOI":"10.1371\/journal.pgen.1000316","volume":"4","author":"D Grote","year":"2008","unstructured":"Grote, D. et al. Gata3 acts downstream of beta-catenin signaling to prevent ectopic metanephric kidney induction. PLoS Genet. 4, e1000316. https:\/\/doi.org\/10.1371\/journal.pgen.1000316 (2008).","journal-title":"PLoS Genet."},{"key":"95427_CR8","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1242\/dev.02184","volume":"133","author":"D Grote","year":"2006","unstructured":"Grote, D., Souabni, A., Busslinger, M. & Bouchard, M. Pax 2\/8-regulated Gata 3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney. Development 133, 53\u201361. https:\/\/doi.org\/10.1242\/dev.02184 (2006).","journal-title":"Development"},{"key":"95427_CR9","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1002\/1096-9861(20010122)429:4<615::aid-cne8>3.0.co;2-f","volume":"429","author":"A Karis","year":"2001","unstructured":"Karis, A. et al. Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear. J. Comp. Neurol. 429, 615\u2013630. https:\/\/doi.org\/10.1002\/1096-9861(20010122)429:4%3c615::aid-cne8%3e3.0.co;2-f (2001).","journal-title":"J. Comp. Neurol."},{"key":"95427_CR10","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1093\/hmg\/ddl454","volume":"16","author":"A Ali","year":"2007","unstructured":"Ali, A. et al. Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: Insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum. Mol. Genet. 16, 265\u2013275. https:\/\/doi.org\/10.1093\/hmg\/ddl454 (2007).","journal-title":"Hum. Mol. Genet."},{"key":"95427_CR11","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/35019088","volume":"406","author":"H Van Esch","year":"2000","unstructured":"Van Esch, H. et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406, 419\u2013422 (2000).","journal-title":"Nature"},{"key":"95427_CR12","doi-asserted-by":"publisher","first-page":"4119","DOI":"10.1242\/dev.01339","volume":"131","author":"KF Barald","year":"2004","unstructured":"Barald, K. F. & Kelley, M. W. From placode to polarization: New tunes in inner ear development. Development 131, 4119\u20134130. https:\/\/doi.org\/10.1242\/dev.01339 (2004).","journal-title":"Development"},{"key":"95427_CR13","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1111\/ede.12015","volume":"15","author":"B Fritzsch","year":"2013","unstructured":"Fritzsch, B. et al. Evolution and development of the tetrapod auditory system: An organ of Corti-centric perspective. Evol. Dev. 15, 63\u201379. https:\/\/doi.org\/10.1111\/ede.12015 (2013).","journal-title":"Evol. Dev."},{"key":"95427_CR14","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1387\/ijdb.103178jd","volume":"55","author":"JS Duncan","year":"2011","unstructured":"Duncan, J. S., Lim, K. C., Engel, J. D. & Fritzsch, B. Limited inner ear morphogenesis and neurosensory development are possible in the absence of GATA3. Int. J. Dev. Biol. 55, 297\u2013303. https:\/\/doi.org\/10.1387\/ijdb.103178jd (2011).","journal-title":"Int. J. Dev. Biol."},{"key":"95427_CR15","doi-asserted-by":"publisher","first-page":"3609","DOI":"10.1093\/hmg\/ddt212","volume":"22","author":"XJ Luo","year":"2013","unstructured":"Luo, X. J. et al. GATA3 controls the specification of prosensory domain and neuronal survival in the mouse cochlea. Hum. Mol. Genet. 22, 3609\u20133623. https:\/\/doi.org\/10.1093\/hmg\/ddt212 (2013).","journal-title":"Hum. Mol. Genet."},{"key":"95427_CR16","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.nbd.2004.02.004","volume":"16","author":"J van der Wees","year":"2004","unstructured":"van der Wees, J. et al. Hearing loss following Gata3 haploinsufficiency is caused by cochlear disorder. Neurobiol. Dis. 16, 169\u2013178. https:\/\/doi.org\/10.1016\/j.nbd.2004.02.004 (2004).","journal-title":"Neurobiol. Dis."},{"key":"95427_CR17","doi-asserted-by":"publisher","first-page":"3679","DOI":"10.1523\/jneurosci.4703-12.2013","volume":"33","author":"JM Appler","year":"2013","unstructured":"Appler, J. M. et al. Gata3 is a critical regulator of cochlear wiring. J. Neurosci. 33, 3679\u20133691. https:\/\/doi.org\/10.1523\/jneurosci.4703-12.2013 (2013).","journal-title":"J. Neurosci."},{"key":"95427_CR18","doi-asserted-by":"publisher","first-page":"e62046","DOI":"10.1371\/journal.pone.0062046","volume":"8","author":"JS Duncan","year":"2013","unstructured":"Duncan, J. S. & Fritzsch, B. Continued expression of GATA3 is necessary for cochlear neurosensory development. PLoS\u00a0One 8, e62046. https:\/\/doi.org\/10.1371\/journal.pone.0062046 (2013).","journal-title":"PLoS\u00a0One"},{"key":"95427_CR19","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/gene.20017","volume":"38","author":"T Ohyama","year":"2004","unstructured":"Ohyama, T. & Groves, A. K. Generation of Pax2-Cre mice by modification of a Pax2 bacterial artificial chromosome. Genesis (New York, NY: 2000) 38, 195\u2013199. https:\/\/doi.org\/10.1002\/gene.20017 (2004).","journal-title":"Genesis (New York, NY: 2000)"},{"key":"95427_CR20","doi-asserted-by":"publisher","first-page":"3389","DOI":"10.1113\/JP277997","volume":"597","author":"T Bardhan","year":"2019","unstructured":"Bardhan, T. et al. Gata3 is required for the functional maturation of inner hair cells and their innervation in the mouse cochlea. J. Physiol. 597, 3389\u20133406. https:\/\/doi.org\/10.1113\/JP277997 (2019).","journal-title":"J. Physiol."},{"key":"95427_CR21","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1242\/dev.103036","volume":"141","author":"BC Cox","year":"2014","unstructured":"Cox, B. C. et al. Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development 141, 816\u2013829. https:\/\/doi.org\/10.1242\/dev.103036 (2014).","journal-title":"Development"},{"key":"95427_CR22","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1172\/jci97248","volume":"128","author":"PJ Atkinson","year":"2018","unstructured":"Atkinson, P. J. et al. Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea. J. Clin. Invest. 128, 1641\u20131656. https:\/\/doi.org\/10.1172\/jci97248 (2018).","journal-title":"J. Clin. Invest."},{"key":"95427_CR23","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.stemcr.2014.01.008","volume":"2","author":"NF Bramhall","year":"2014","unstructured":"Bramhall, N. F., Shi, F., Arnold, K., Hochedlinger, K. & Edge, A. S. Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea. Stem Cell Rep. 2, 311\u2013322. https:\/\/doi.org\/10.1016\/j.stemcr.2014.01.008 (2014).","journal-title":"Stem Cell Rep."},{"key":"95427_CR24","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1073\/pnas.1415901112","volume":"112","author":"W Li","year":"2015","unstructured":"Li, W. et al. Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc. Natl. Acad. Sci. USA 112, 166\u2013171. https:\/\/doi.org\/10.1073\/pnas.1415901112 (2015).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"95427_CR25","doi-asserted-by":"publisher","first-page":"8734","DOI":"10.1523\/JNEUROSCI.0060-16.2016","volume":"36","author":"W Ni","year":"2016","unstructured":"Ni, W. et al. Extensive supporting cell proliferation and mitotic hair cell generation by in vivo genetic reprogramming in the neonatal mouse cochlea. J. Neurosci. 36, 8734\u20138745. https:\/\/doi.org\/10.1523\/JNEUROSCI.0060-16.2016 (2016).","journal-title":"J. Neurosci."},{"key":"95427_CR26","doi-asserted-by":"publisher","first-page":"10530","DOI":"10.1523\/JNEUROSCI.0686-12.2012","volume":"32","author":"Z Liu","year":"2012","unstructured":"Liu, Z. et al. Regulation of p27Kip1 by Sox2 maintains quiescence of inner pillar cells in the murine auditory sensory epithelium. J. Neurosci. 32, 10530\u201310540. https:\/\/doi.org\/10.1523\/JNEUROSCI.0686-12.2012 (2012).","journal-title":"J. Neurosci."},{"key":"95427_CR27","doi-asserted-by":"publisher","first-page":"4084","DOI":"10.1073\/pnas.96.7.4084","volume":"96","author":"H L\u00f6wenheim","year":"1999","unstructured":"L\u00f6wenheim, H. et al. Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. Proc. Natl. Acad. Sci. USA 96, 4084\u20134088 (1999).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"95427_CR28","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.4161\/cc.10.8.15301","volume":"10","author":"EC Oesterle","year":"2011","unstructured":"Oesterle, E. C., Chien, W. M., Campbell, S., Nellimarla, P. & Fero, M. L. p27(Kip1) is required to maintain proliferative quiescence in the adult cochlea and pituitary. Cell Cycle 10, 1237\u20131248. https:\/\/doi.org\/10.4161\/cc.10.8.15301 (2011).","journal-title":"Cell Cycle"},{"key":"95427_CR29","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1084\/jem.20171127","volume":"215","author":"D Fang","year":"2018","unstructured":"Fang, D. et al. Bcl11b, a novel GATA3-interacting protein, suppresses Th1 while limiting Th2 cell differentiation. J. Exp. Med. 215, 1449\u20131462. https:\/\/doi.org\/10.1084\/jem.20171127 (2018).","journal-title":"J. Exp. Med."},{"key":"95427_CR30","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1242\/dev.145318","volume":"144","author":"P Home","year":"2017","unstructured":"Home, P. et al. Genetic redundancy of GATA factors in the extraembryonic trophoblast lineage ensures the progression of preimplantation and postimplantation mammalian development. Development 144, 876\u2013888. https:\/\/doi.org\/10.1242\/dev.145318 (2017).","journal-title":"Development"},{"key":"95427_CR31","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.immuni.2011.08.007","volume":"35","author":"G Wei","year":"2011","unstructured":"Wei, G. et al. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 35, 299\u2013311. https:\/\/doi.org\/10.1016\/j.immuni.2011.08.007 (2011).","journal-title":"Immunity"},{"key":"95427_CR32","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1101\/gr.229102","volume":"12","author":"WJ Kent","year":"2002","unstructured":"Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996\u20131006 (2002).","journal-title":"Genome Res."},{"key":"95427_CR33","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.molcel.2010.05.004","volume":"38","author":"S Heinz","year":"2010","unstructured":"Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576\u2013589. https:\/\/doi.org\/10.1016\/j.molcel.2010.05.004 (2010).","journal-title":"Mol. Cell"},{"key":"95427_CR34","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1093\/bioinformatics\/btr064","volume":"27","author":"CE Grant","year":"2011","unstructured":"Grant, C. E., Bailey, T. L. & Noble, W. S. FIMO: Scanning for occurrences of a given motif. Bioinformatics 27, 1017\u20131018. https:\/\/doi.org\/10.1093\/bioinformatics\/btr064 (2011).","journal-title":"Bioinformatics"},{"key":"95427_CR35","doi-asserted-by":"publisher","first-page":"D260","DOI":"10.1093\/nar\/gkx1126","volume":"46","author":"A Khan","year":"2018","unstructured":"Khan, A. et al. JASPAR 2018: Update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Res. 46, D260\u2013D266. https:\/\/doi.org\/10.1093\/nar\/gkx1126 (2018).","journal-title":"Nucleic Acids Res."},{"key":"95427_CR36","doi-asserted-by":"publisher","first-page":"11621","DOI":"10.1038\/srep11621","volume":"5","author":"BJ Walters","year":"2015","unstructured":"Walters, B. J., Yamashita, T. & Zuo, J. Sox2-CreER mice are useful for fate mapping of mature, but not neonatal, cochlear supporting cells in hair cell regeneration studies. Sci. Rep. 5, 11621. https:\/\/doi.org\/10.1038\/srep11621 (2015).","journal-title":"Sci. Rep."},{"key":"95427_CR37","doi-asserted-by":"publisher","first-page":"23293","DOI":"10.1038\/srep23293","volume":"6","author":"JS Kempfle","year":"2016","unstructured":"Kempfle, J. S., Turban, J. L. & Edge, A. S. Sox2 in the differentiation of cochlear progenitor cells. Sci. Rep. 6, 23293. https:\/\/doi.org\/10.1038\/srep23293 (2016).","journal-title":"Sci. Rep."},{"key":"95427_CR38","doi-asserted-by":"publisher","first-page":"2817","DOI":"10.1242\/dev.02453","volume":"133","author":"YS Lee","year":"2006","unstructured":"Lee, Y. S., Liu, F. & Segil, N. A morphogenetic wave of p27Kip1 transcription directs cell cycle exit during organ of Corti development. Development 133, 2817\u20132826. https:\/\/doi.org\/10.1242\/dev.02453 (2006).","journal-title":"Development"},{"key":"95427_CR39","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1288\/00005537-197110000-00018","volume":"81","author":"RJ Ruben","year":"1971","unstructured":"Ruben, R. J., Van de Water, T. & Polesky, A. Cell kinetics of the 11 and 12-day mouse otocysts. Laryngoscope 81, 1708\u20131718. https:\/\/doi.org\/10.1288\/00005537-197110000-00018 (1971).","journal-title":"Laryngoscope"},{"key":"95427_CR40","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1002\/dvdy.20551","volume":"234","author":"V Matei","year":"2005","unstructured":"Matei, V. et al. Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit. Dev. Dyn. 234, 633\u2013650. https:\/\/doi.org\/10.1002\/dvdy.20551 (2005).","journal-title":"Dev. Dyn."},{"key":"95427_CR41","doi-asserted-by":"publisher","first-page":"5927","DOI":"10.1523\/jneurosci.5989-09.2010","volume":"30","author":"Y Yu","year":"2010","unstructured":"Yu, Y. et al. In vivo proliferation of postmitotic cochlear supporting cells by acute ablation of the retinoblastoma protein in neonatal mice. J. Neurosci. 30, 5927\u20135936. https:\/\/doi.org\/10.1523\/jneurosci.5989-09.2010 (2010).","journal-title":"J. Neurosci."},{"key":"95427_CR42","doi-asserted-by":"publisher","first-page":"18396","DOI":"10.1073\/pnas.0808175105","volume":"105","author":"A Dabdoub","year":"2008","unstructured":"Dabdoub, A. et al. Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea. Proc. Natl. Acad. Sci. USA 105, 18396\u201318401. https:\/\/doi.org\/10.1073\/pnas.0808175105 (2008).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"95427_CR43","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.ydbio.2019.09.003","volume":"457","author":"M Dvorakova","year":"2020","unstructured":"Dvorakova, M. et al. Early ear neuronal development, but not olfactory or lens development, can proceed without SOX2. Dev. Biol. 457, 43\u201356. https:\/\/doi.org\/10.1016\/j.ydbio.2019.09.003 (2020).","journal-title":"Dev. Biol."},{"key":"95427_CR44","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1038\/nature03487","volume":"434","author":"AE Kiernan","year":"2005","unstructured":"Kiernan, A. E. et al. Sox2 is required for sensory organ development in the mammalian inner ear. Nature 434, 1031\u20131035. https:\/\/doi.org\/10.1038\/nature03487 (2005).","journal-title":"Nature"},{"key":"95427_CR45","doi-asserted-by":"publisher","first-page":"13851","DOI":"10.1073\/pnas.1219952110","volume":"110","author":"F Shi","year":"2013","unstructured":"Shi, F., Hu, L. & Edge, A. S. Generation of hair cells in neonatal mice by beta-catenin overexpression in Lgr5-positive cochlear progenitors. Proc. Natl. Acad. Sci. USA 110, 13851\u201313856. https:\/\/doi.org\/10.1073\/pnas.1219952110 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"95427_CR46","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/s1567-133x(03)00089-9","volume":"3","author":"EA Lumpkin","year":"2003","unstructured":"Lumpkin, E. A. et al. Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Express. Patterns 3, 389\u2013395. https:\/\/doi.org\/10.1016\/s1567-133x(03)00089-9 (2003).","journal-title":"Gene Express. Patterns"},{"key":"95427_CR47","doi-asserted-by":"publisher","first-page":"9469","DOI":"10.1523\/JNEUROSCI.23-28-09469.2003","volume":"23","author":"M Montcouquiol","year":"2003","unstructured":"Montcouquiol, M. & Kelley, M. W. Planar and vertical signals control cellular differentiation and patterning in the mammalian cochlea. J. Neurosci. 23, 9469\u20139478 (2003).","journal-title":"J. Neurosci."},{"key":"95427_CR48","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.celrep.2017.03.044","volume":"19","author":"BJ Walters","year":"2017","unstructured":"Walters, B. J. et al. In vivo interplay between p27(Kip1), GATA3, ATOH1, and POU4F3 converts non-sensory cells to hair cells in adult mice. Cell Rep. 19, 307\u2013320. https:\/\/doi.org\/10.1016\/j.celrep.2017.03.044 (2017).","journal-title":"Cell Rep."},{"key":"95427_CR49","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/ncomms1094","volume":"1","author":"R Ghaffari","year":"2010","unstructured":"Ghaffari, R., Aranyosi, A. J., Richardson, G. P. & Freeman, D. M. Tectorial membrane travelling waves underlie abnormal hearing in Tectb mutant mice. Nat. Commun. 1, 96. https:\/\/doi.org\/10.1038\/ncomms1094 (2010).","journal-title":"Nat. Commun."},{"key":"95427_CR50","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nn1828","volume":"10","author":"IJ Russell","year":"2007","unstructured":"Russell, I. J. et al. Sharpened cochlear tuning in a mouse with a genetically modified tectorial membrane. Nat. Neurosci. 10, 215\u2013223. https:\/\/doi.org\/10.1038\/nn1828 (2007).","journal-title":"Nat. Neurosci."},{"key":"95427_CR51","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1002\/cne.20936","volume":"496","author":"R Romand","year":"2006","unstructured":"Romand, R. et al. Dynamic expression of retinoic acid-synthesizing and -metabolizing enzymes in the developing mouse inner ear. J. Comp. Neurol. 496, 643\u2013654. https:\/\/doi.org\/10.1002\/cne.20936 (2006).","journal-title":"J. Comp. Neurol."},{"key":"95427_CR52","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.modgep.2003.09.006","volume":"4","author":"R Romand","year":"2004","unstructured":"Romand, R. et al. Complementary expression patterns of retinoid acid-synthesizing and -metabolizing enzymes in pre-natal mouse inner ear structures. Gene Express. Patterns 4, 123\u2013133. https:\/\/doi.org\/10.1016\/j.modgep.2003.09.006 (2004).","journal-title":"Gene Express. Patterns"},{"key":"95427_CR53","doi-asserted-by":"publisher","first-page":"e7786","DOI":"10.1371\/journal.pone.0007786.g001","volume":"4","author":"K Katayama","year":"2009","unstructured":"Katayama, K. et al. Disorganized innervation and neuronal loss in the inner ear of Slitrk6-deficient mice. PLoS\u00a0One 4, e7786. https:\/\/doi.org\/10.1371\/journal.pone.0007786.g001 (2009).","journal-title":"PLoS\u00a0One"},{"key":"95427_CR54","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1016\/j.cell.2015.10.070","volume":"163","author":"HC Wang","year":"2015","unstructured":"Wang, H. C. et al. Spontaneous activity of cochlear hair cells triggered by fluid secretion mechanism in adjacent support cells. Cell 163, 1348\u20131359. https:\/\/doi.org\/10.1016\/j.cell.2015.10.070 (2015).","journal-title":"Cell"},{"key":"95427_CR55","doi-asserted-by":"publisher","first-page":"2571","DOI":"10.1007\/s00424-015-1720-6","volume":"467","author":"A Eckhard","year":"2015","unstructured":"Eckhard, A. et al. Regulation of the perilymphatic-endolymphatic water shunt in the cochlea by membrane translocation of aquaporin-5. Pflugers Arch. 467, 2571\u20132588. https:\/\/doi.org\/10.1007\/s00424-015-1720-6 (2015).","journal-title":"Pflugers Arch."},{"key":"95427_CR56","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s00441-012-1456-y","volume":"350","author":"A Eckhard","year":"2012","unstructured":"Eckhard, A. et al. Co-localisation of K(ir)4.1 and AQP4 in rat and human cochleae reveals a gap in water channel expression at the transduction sites of endocochlear K(+) recycling routes. Cell Tissue Res. 350, 27\u201343. https:\/\/doi.org\/10.1007\/s00441-012-1456-y (2012).","journal-title":"Cell Tissue Res."},{"key":"95427_CR57","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.stem.2011.09.001","volume":"9","author":"K Arnold","year":"2011","unstructured":"Arnold, K. et al. Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9, 317\u2013329. https:\/\/doi.org\/10.1016\/j.stem.2011.09.001 (2011).","journal-title":"Cell Stem Cell"},{"key":"95427_CR58","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ydbio.2009.11.003","volume":"338","author":"M Deng","year":"2010","unstructured":"Deng, M., Pan, L., Xie, X. & Gan, L. Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear. Dev. Biol. 338, 38\u201349. https:\/\/doi.org\/10.1016\/j.ydbio.2009.11.003 (2010).","journal-title":"Dev. Biol."},{"key":"95427_CR59","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1186\/1756-0500-5-109","volume":"5","author":"R Schuch","year":"2012","unstructured":"Schuch, R. et al. Site-specific chromatin immunoprecipitation: A selective method to individually analyze neighboring transcription factor binding sites in vivo. BMC Res. Notes 5, 109. https:\/\/doi.org\/10.1186\/1756-0500-5-109 (2012).","journal-title":"BMC Res. Notes"},{"key":"95427_CR60","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1038\/nprot.2012.016","volume":"7","author":"C Trapnell","year":"2012","unstructured":"Trapnell, C. et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562\u2013578. https:\/\/doi.org\/10.1038\/nprot.2012.016 (2012).","journal-title":"Nat. Protoc."},{"key":"95427_CR61","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq\u2014a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169. https:\/\/doi.org\/10.1093\/bioinformatics\/btu638 (2015).","journal-title":"Bioinformatics"},{"key":"95427_CR62","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550. https:\/\/doi.org\/10.1186\/s13059-014-0550-8 (2014).","journal-title":"Genome Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95427-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95427-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95427-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T12:02:53Z","timestamp":1670068973000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95427-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,4]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["95427"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-95427-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,4]]},"assertion":[{"value":"20 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15779"}}