{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T16:13:57Z","timestamp":1794500037271,"version":"4.9.1"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T00:00:00Z","timestamp":1607385600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T00:00:00Z","timestamp":1607385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R01-DC014832"],"award-info":[{"award-number":["R01-DC014832"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R21-DC016171"],"award-info":[{"award-number":["R21-DC016171"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor <jats:italic>Atoh1,<\/jats:italic> but to date this approach has yielded low and variable efficiency of HC production. <jats:italic>Gfi1<\/jats:italic> is a transcription factor important for HC development and survival. We evaluated the combinatorial effects of <jats:italic>Atoh1<\/jats:italic> and <jats:italic>Gfi1<\/jats:italic> over-expression on HC regeneration using gene transfer methods in neonatal cochlear explants, and in vivo in adult mice. Adenoviral over-expression of <jats:italic>Atoh1<\/jats:italic> and <jats:italic>Gfi1<\/jats:italic> in cultured neonatal cochlear explants resulted in numerous ectopic HC-like cells (HCLCs), with significantly more cells in <jats:italic>Atoh1<\/jats:italic>\u2009+\u2009<jats:italic>Gfi1<\/jats:italic> cultures than <jats:italic>Atoh1<\/jats:italic> alone. In vitro, ectopic HCLCs emerged in regions medial to inner HCs as well as in the stria vascularis. In vivo experiments were performed in mature Pou4f3<jats:sup>DTR<\/jats:sup> mice in which HCs were completely and specifically ablated by administration of diphtheria toxin. Adenoviral expression of <jats:italic>Atoh1<\/jats:italic> or <jats:italic>Atoh1<\/jats:italic>\u2009+\u2009<jats:italic>Gfi1<\/jats:italic> in cochlear supporting cells induced appearance of HCLCs, with <jats:italic>Atoh1<\/jats:italic>\u2009+\u2009<jats:italic>Gfi1<\/jats:italic> expression leading to 6.2-fold increase of new HCLCs after 4\u00a0weeks compared to <jats:italic>Atoh1<\/jats:italic> alone. New HCLCs were detected throughout the cochlea, exhibited immature stereocilia and survived for at least 8\u00a0weeks. Combinatorial <jats:italic>Atoh1<\/jats:italic> and <jats:italic>Gfi1<\/jats:italic> induction is thus a promising strategy to promote HC regeneration in the mature mammalian cochlea.<\/jats:p>","DOI":"10.1038\/s41598-020-78167-8","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T11:04:42Z","timestamp":1607425482000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea"],"prefix":"10.1038","volume":"10","author":[{"given":"Sungsu","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Jun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A.","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald L.","family":"Swiderski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane M.","family":"Prieskorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melih","family":"Acar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-I","family":"Jen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew K.","family":"Groves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehoash","family":"Raphael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,8]]},"reference":[{"key":"78167_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1007\/s00441-015-2113-z","volume":"361","author":"DN Furness","year":"2015","unstructured":"Furness, D. N. Molecular basis of hair cell loss. Cell Tissue Res. 361, 387\u2013399. https:\/\/doi.org\/10.1007\/s00441-015-2113-z (2015).","journal-title":"Cell Tissue Res."},{"key":"78167_CR2","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.otc.2018.01.006","volume":"51","author":"CS Brown","year":"2018","unstructured":"Brown, C. S., Emmett, S. D., Robler, S. K. & Tucci, D. L. Global hearing loss prevention. Otolaryngol. Clin. North Am. 51, 575\u2013592. https:\/\/doi.org\/10.1016\/j.otc.2018.01.006 (2018).","journal-title":"Otolaryngol. Clin. North Am."},{"key":"78167_CR3","doi-asserted-by":"publisher","first-page":"E1383","DOI":"10.1073\/pnas.1402898111","volume":"111","author":"L Jiang","year":"2014","unstructured":"Jiang, L., Romero-Carvajal, A., Haug, J. S., Seidel, C. W. & Piotrowski, T. Gene-expression analysis of hair cell regeneration in the zebrafish lateral line. Proc. Natl. Acad. Sci. U.S.A. 111, E1383\u2013E1392. https:\/\/doi.org\/10.1073\/pnas.1402898111 (2014).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"78167_CR4","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44431","author":"ME Lush","year":"2019","unstructured":"Lush, M. E. et al. scRNA-Seq reveals distinct stem cell populations that drive hair cell regeneration after loss of Fgf and Notch signaling. Elife https:\/\/doi.org\/10.7554\/eLife.44431 (2019).","journal-title":"Elife"},{"key":"78167_CR5","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.devcel.2015.05.025","volume":"34","author":"A Romero-Carvajal","year":"2015","unstructured":"Romero-Carvajal, A. et al. Regeneration of sensory hair cells requires localized interactions between the Notch and Wnt pathways. Dev. Cell 34, 267\u2013282. https:\/\/doi.org\/10.1016\/j.devcel.2015.05.025 (2015).","journal-title":"Dev. Cell"},{"key":"78167_CR6","doi-asserted-by":"publisher","first-page":"2261","DOI":"10.1523\/JNEUROSCI.4372-07.2008","volume":"28","author":"EY Ma","year":"2008","unstructured":"Ma, E. Y., Rubel, E. W. & Raible, D. W. Notch signaling regulates the extent of hair cell regeneration in the zebrafish lateral line. J. Neurosci. 28, 2261\u20132273. https:\/\/doi.org\/10.1523\/JNEUROSCI.4372-07.2008 (2008).","journal-title":"J. Neurosci."},{"key":"78167_CR7","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a033183","author":"AS Janesick","year":"2019","unstructured":"Janesick, A. S. & Heller, S. Stem cells and the bird cochlea-where is everybody?. Cold Spring Harb. Perspect. Med. https:\/\/doi.org\/10.1101\/cshperspect.a033183 (2019).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"78167_CR8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.gde.2016.05.012","volume":"40","author":"JS Kniss","year":"2016","unstructured":"Kniss, J. S., Jiang, L. & Piotrowski, T. Insights into sensory hair cell regeneration from the zebrafish lateral line. Curr. Opin. Genet. Dev. 40, 32\u201340. https:\/\/doi.org\/10.1016\/j.gde.2016.05.012 (2016).","journal-title":"Curr. Opin. Genet. Dev."},{"key":"78167_CR9","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1126\/science.284.5421.1837","volume":"284","author":"NA Bermingham","year":"1999","unstructured":"Bermingham, N. A. et al. Math1: an essential gene for the generation of inner ear hair cells. Science 284, 1837\u20131841 (1999).","journal-title":"Science"},{"key":"78167_CR10","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1038\/nn1349","volume":"7","author":"C Woods","year":"2004","unstructured":"Woods, C., Montcouquiol, M. & Kelley, M. W. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat. Neurosci. 7, 1310\u20131318 (2004).","journal-title":"Nat. Neurosci."},{"key":"78167_CR11","doi-asserted-by":"publisher","first-page":"10110","DOI":"10.1523\/JNEUROSCI.5606-12.2013","volume":"33","author":"T Cai","year":"2013","unstructured":"Cai, T., Seymour, M. L., Zhang, H., Pereira, F. A. & Groves, A. K. Conditional deletion of Atoh1 reveals distinct critical periods for survival and function of hair cells in the organ of Corti. J. Neurosci. 33, 10110\u201310122. https:\/\/doi.org\/10.1523\/JNEUROSCI.5606-12.2013 (2013).","journal-title":"J. Neurosci."},{"key":"78167_CR12","doi-asserted-by":"publisher","first-page":"e30358","DOI":"10.1371\/journal.pone.0030358","volume":"7","author":"N Pan","year":"2012","unstructured":"Pan, N. et al. A novel Atoh1 \u201cself-terminating\u201d mouse model reveals the necessity of proper Atoh1 level and duration for hair cell differentiation and viability. PLoS ONE 7, e30358. https:\/\/doi.org\/10.1371\/journal.pone.0030358 (2012).","journal-title":"PLoS ONE"},{"key":"78167_CR13","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/75753","volume":"3","author":"JL Zheng","year":"2000","unstructured":"Zheng, J. L. & Gao, W. Q. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat. Neurosci. 3, 580\u2013586. https:\/\/doi.org\/10.1038\/75753 (2000).","journal-title":"Nat. Neurosci."},{"key":"78167_CR14","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/nature07265","volume":"455","author":"SP Gubbels","year":"2008","unstructured":"Gubbels, S. P., Woessner, D. W., Mitchell, J. C., Ricci, A. J. & Brigande, J. V. Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature 455, 537\u2013541. https:\/\/doi.org\/10.1038\/nature07265 (2008).","journal-title":"Nature"},{"key":"78167_CR15","doi-asserted-by":"publisher","first-page":"4395","DOI":"10.1523\/JNEUROSCI.23-11-04395.2003","volume":"23","author":"K Kawamoto","year":"2003","unstructured":"Kawamoto, K., Ishimoto, S., Minoda, R., Brough, D. E. & Raphael, Y. Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J. Neurosci. 23, 4395\u20134400 (2003).","journal-title":"J. Neurosci."},{"key":"78167_CR16","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/nm1193","volume":"11","author":"M Izumikawa","year":"2005","unstructured":"Izumikawa, M. et al. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat. Med. 11, 271\u2013276. https:\/\/doi.org\/10.1038\/nm1193 (2005).","journal-title":"Nat. Med."},{"key":"78167_CR17","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.jcomdis.2010.04.001","volume":"43","author":"SB Shibata","year":"2010","unstructured":"Shibata, S. B. & Raphael, Y. Future approaches for inner ear protection and repair. J. Commun. Disord. 43, 295\u2013310. https:\/\/doi.org\/10.1016\/j.jcomdis.2010.04.001 (2010).","journal-title":"J. Commun. Disord."},{"key":"78167_CR18","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.semcdb.2016.11.002","volume":"65","author":"A Doetzlhofer","year":"2017","unstructured":"Doetzlhofer, A. & Avraham, K. B. Insights into inner ear-specific gene regulation: epigenetics and non-coding RNAs in inner ear development and regeneration. Semin. Cell Dev. Biol. 65, 69\u201379. https:\/\/doi.org\/10.1016\/j.semcdb.2016.11.002 (2017).","journal-title":"Semin. Cell Dev. Biol."},{"key":"78167_CR19","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1242\/dev.137976","volume":"143","author":"ZP Stojanova","year":"2016","unstructured":"Stojanova, Z. P., Kwan, T. & Segil, N. Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea. Development 143, 1632. https:\/\/doi.org\/10.1242\/dev.137976 (2016).","journal-title":"Development"},{"key":"78167_CR20","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.neuron.2012.10.032","volume":"77","author":"K Mizutari","year":"2013","unstructured":"Mizutari, K. et al. Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 77, 58\u201369. https:\/\/doi.org\/10.1016\/j.neuron.2012.10.032 (2013).","journal-title":"Neuron"},{"key":"78167_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2020.107981","author":"SB Shibata","year":"2020","unstructured":"Shibata, S. B. et al. Gene therapy for hair cell regeneration: review and new data. Hear. Res. https:\/\/doi.org\/10.1016\/j.heares.2020.107981 (2020).","journal-title":"Hear. Res."},{"key":"78167_CR22","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1016\/j.ymthe.2018.03.004","volume":"26","author":"X Du","year":"2018","unstructured":"Du, X. et al. Regeneration of cochlear hair cells and hearing recovery through Hes1 modulation with siRNA nanoparticles in adult guinea pigs. Mol. Ther. 26, 1313\u20131326. https:\/\/doi.org\/10.1016\/j.ymthe.2018.03.004 (2018).","journal-title":"Mol. Ther."},{"key":"78167_CR23","doi-asserted-by":"publisher","first-page":"110","DOI":"10.3389\/fncel.2015.00110","volume":"9","author":"JC Maass","year":"2015","unstructured":"Maass, J. C. et al. Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea. Front. Cell. Neurosci. 9, 110. https:\/\/doi.org\/10.3389\/fncel.2015.00110 (2015).","journal-title":"Front. Cell. Neurosci."},{"key":"78167_CR24","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/nrm.2016.8","volume":"17","author":"K Takahashi","year":"2016","unstructured":"Takahashi, K. & Yamanaka, S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 17, 183\u2013193. https:\/\/doi.org\/10.1038\/nrm.2016.8 (2016).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"78167_CR25","doi-asserted-by":"publisher","first-page":"2877","DOI":"10.1002\/cne.23620","volume":"522","author":"CE Ang","year":"2014","unstructured":"Ang, C. E. & Wernig, M. Induced neuronal reprogramming. J. Comp. Neurol. 522, 2877\u20132886. https:\/\/doi.org\/10.1002\/cne.23620 (2014).","journal-title":"J. Comp. Neurol."},{"key":"78167_CR26","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1016\/j.cell.2016.08.055","volume":"166","author":"D Srivastava","year":"2016","unstructured":"Srivastava, D. & DeWitt, N. In vivo cellular reprogramming: the next generation. Cell 166, 1386\u20131396. https:\/\/doi.org\/10.1016\/j.cell.2016.08.055 (2016).","journal-title":"Cell"},{"key":"78167_CR27","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1016\/j.ymthe.2019.03.017","volume":"27","author":"A Samarajeewa","year":"2019","unstructured":"Samarajeewa, A., Jacques, B. E. & Dabdoub, A. Therapeutic potential of Wnt and notch signaling and epigenetic regulation in mammalian sensory hair cell regeneration. Mol. Ther. 27, 904\u2013911. https:\/\/doi.org\/10.1016\/j.ymthe.2019.03.017 (2019).","journal-title":"Mol. Ther."},{"key":"78167_CR28","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":"78167_CR29","doi-asserted-by":"publisher","first-page":"5530","DOI":"10.1038\/s41467-019-13157-7","volume":"10","author":"Y Shu","year":"2019","unstructured":"Shu, Y. et al. Renewed proliferation in adult mouse cochlea and regeneration of hair cells. Nat. Commun. 10, 5530. https:\/\/doi.org\/10.1038\/s41467-019-13157-7 (2019).","journal-title":"Nat. Commun."},{"key":"78167_CR30","doi-asserted-by":"publisher","first-page":"e1007552","DOI":"10.1371\/journal.pgen.1007552","volume":"14","author":"T Yamashita","year":"2018","unstructured":"Yamashita, T. et al. High-resolution transcriptional dissection of in vivo Atoh1-mediated hair cell conversion in mature cochleae identifies Isl1 as a co-reprogramming factor. PLoS Genet. 14, e1007552. https:\/\/doi.org\/10.1371\/journal.pgen.1007552 (2018).","journal-title":"PLoS Genet."},{"key":"78167_CR31","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1080\/14712598.2019.1564035","volume":"19","author":"PJ Atkinson","year":"2019","unstructured":"Atkinson, P. J., Kim, G. S. & Cheng, A. G. Direct cellular reprogramming and inner ear regeneration. Expert Opin. Biol. Ther. 19, 129\u2013139. https:\/\/doi.org\/10.1080\/14712598.2019.1564035 (2019).","journal-title":"Expert Opin. Biol. Ther."},{"key":"78167_CR32","doi-asserted-by":"publisher","first-page":"4116","DOI":"10.1038\/sj.emboj.7600419","volume":"23","author":"H Zeng","year":"2004","unstructured":"Zeng, H., Yucel, R., Kosan, C., Klein-Hitpass, L. & Moroy, T. Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells. EMBO J. 23, 4116\u20134125. https:\/\/doi.org\/10.1038\/sj.emboj.7600419 (2004).","journal-title":"EMBO J."},{"key":"78167_CR33","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/s0092-8674(00)00040-4","volume":"102","author":"R Nolo","year":"2000","unstructured":"Nolo, R., Abbott, L. A. & Bellen, H. J. Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila. Cell 102, 349\u2013362. https:\/\/doi.org\/10.1016\/s0092-8674(00)00040-4 (2000).","journal-title":"Cell"},{"key":"78167_CR34","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1242\/dev.00190","volume":"130","author":"D Wallis","year":"2003","unstructured":"Wallis, D. et al. The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival. Development 130, 221\u2013232 (2003).","journal-title":"Development"},{"key":"78167_CR35","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1093\/hmg\/ddh218","volume":"13","author":"R Hertzano","year":"2004","unstructured":"Hertzano, R. et al. Transcription profiling of inner ears from Pou4f3(ddl\/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum. Mol. Genet. 13, 2143\u20132153 (2004).","journal-title":"Hum. Mol. Genet."},{"key":"78167_CR36","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1111\/j.1460-9568.2007.05332.x","volume":"25","author":"R Hertzano","year":"2007","unstructured":"Hertzano, R. et al. Lhx3, a LIM domain transcription factor, is regulated by Pou4f3 in the auditory but not in the vestibular system. Eur. J. Neurosci. 25, 999\u20131005 (2007).","journal-title":"Eur. J. Neurosci."},{"key":"78167_CR37","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1007\/s12035-014-8801-y","volume":"51","author":"R Ikeda","year":"2015","unstructured":"Ikeda, R., Pak, K., Chavez, E. & Ryan, A. F. Transcription factors with conserved binding sites near ATOH1 on the POU4F3 gene enhance the induction of cochlear hair cells. Mol. Neurobiol. 51, 672\u2013684. https:\/\/doi.org\/10.1007\/s12035-014-8801-y (2015).","journal-title":"Mol. Neurobiol."},{"key":"78167_CR38","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.gdata.2015.08.017","volume":"6","author":"A Costa","year":"2015","unstructured":"Costa, A. & Henrique, D. Transcriptome profiling of induced hair cells (iHCs) generated by combined expression of Gfi1, Pou4f3 and Atoh1 during embryonic stem cell differentiation. Genomics Data 6, 77\u201380. https:\/\/doi.org\/10.1016\/j.gdata.2015.08.017 (2015).","journal-title":"Genomics Data"},{"key":"78167_CR39","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55249","author":"L Menendez","year":"2020","unstructured":"Menendez, L. et al. Generation of inner ear hair cells by direct lineage conversion of primary somatic cells. Elife https:\/\/doi.org\/10.7554\/eLife.55249 (2020).","journal-title":"Elife"},{"key":"78167_CR40","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.neuroscience.2016.07.001","volume":"332","author":"T Kurioka","year":"2016","unstructured":"Kurioka, T. et al. Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus. Neuroscience 332, 242\u2013257. https:\/\/doi.org\/10.1016\/j.neuroscience.2016.07.001 (2016).","journal-title":"Neuroscience"},{"key":"78167_CR41","doi-asserted-by":"publisher","first-page":"7878","DOI":"10.1523\/JNEUROSCI.2179-14.2015","volume":"35","author":"L Tong","year":"2015","unstructured":"Tong, L. et al. Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons. J. Neurosci. 35, 7878\u20137891. https:\/\/doi.org\/10.1523\/JNEUROSCI.2179-14.2015 (2015).","journal-title":"J. Neurosci."},{"key":"78167_CR42","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/S0378-5955(02)00579-8","volume":"173","author":"S Ishimoto","year":"2002","unstructured":"Ishimoto, S., Kawamoto, K., Kanzaki, S. & Raphael, Y. Gene transfer into supporting cells of the organ of Corti. Hear. Res. 173, 187\u2013197 (2002).","journal-title":"Hear. Res."},{"key":"78167_CR43","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1016\/j.cell.2010.03.049","volume":"141","author":"S Kitajiri","year":"2010","unstructured":"Kitajiri, S. et al. Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing. Cell 141, 786\u2013798. https:\/\/doi.org\/10.1016\/j.cell.2010.03.049 (2010).","journal-title":"Cell"},{"key":"78167_CR44","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":"78167_CR45","doi-asserted-by":"publisher","first-page":"19484","DOI":"10.1038\/srep19484","volume":"6","author":"DP Campbell","year":"2016","unstructured":"Campbell, D. P., Chrysostomou, E. & Doetzlhofer, A. Canonical Notch signaling plays an instructive role in auditory supporting cell development. Sci. Rep. 6, 19484. https:\/\/doi.org\/10.1038\/srep19484 (2016).","journal-title":"Sci. Rep."},{"key":"78167_CR46","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/nature23283","volume":"548","author":"NL Jorstad","year":"2017","unstructured":"Jorstad, N. L. et al. Stimulation of functional neuronal regeneration from Muller glia in adult mice. Nature 548, 103\u2013107. https:\/\/doi.org\/10.1038\/nature23283 (2017).","journal-title":"Nature"},{"key":"78167_CR47","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.heares.2007.06.005","volume":"232","author":"R Minoda","year":"2007","unstructured":"Minoda, R., Izumikawa, M., Kawamoto, K., Zhang, H. & Raphael, Y. Manipulating cell cycle regulation in the mature cochlea. Hear. Res. 232, 44\u201351. https:\/\/doi.org\/10.1016\/j.heares.2007.06.005 (2007).","journal-title":"Hear. Res."},{"key":"78167_CR48","doi-asserted-by":"publisher","first-page":"8803","DOI":"10.1128\/MCB.24.20.8803-8812.2004","volume":"24","author":"H Jafar-Nejad","year":"2004","unstructured":"Jafar-Nejad, H. & Bellen, H. J. Gfi\/Pag-3\/senseless zinc finger proteins: a unifying theme?. Mol. Cell. Biol. 24, 8803\u20138812. https:\/\/doi.org\/10.1128\/MCB.24.20.8803-8812.2004 (2004).","journal-title":"Mol. Cell. Biol."},{"key":"78167_CR49","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/s0896-6273(01)00367-1","volume":"31","author":"K Gowan","year":"2001","unstructured":"Gowan, K. et al. Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31, 219\u2013232. https:\/\/doi.org\/10.1016\/s0896-6273(01)00367-1 (2001).","journal-title":"Neuron"},{"key":"78167_CR50","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1242\/dev.125.5.919","volume":"125","author":"AW Helms","year":"1998","unstructured":"Helms, A. W. & Johnson, J. E. Progenitors of dorsal commissural interneurons are defined by MATH1 expression. Development 125, 919\u2013928 (1998).","journal-title":"Development"},{"key":"78167_CR51","doi-asserted-by":"publisher","DOI":"10.1101\/767574","author":"A Costa","year":"2019","unstructured":"Costa, A., Powell, L. M., Soufi, A., Lowell, S. & Jarman, A. P. Atoh1 is repurposed from neuronal to hair cell determinant by Gfi1 acting as a coactivator without redistribution of its genomic binding sites. bioRxiv https:\/\/doi.org\/10.1101\/767574 (2019).","journal-title":"bioRxiv"},{"key":"78167_CR52","doi-asserted-by":"publisher","DOI":"10.1242\/dev.186015","author":"MS Matern","year":"2020","unstructured":"Matern, M. S. et al. GFI1 functions to repress neuronal gene expression in the developing inner ear hair cells. Development https:\/\/doi.org\/10.1242\/dev.186015 (2020).","journal-title":"Development"},{"key":"78167_CR53","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1002\/jcb.10548","volume":"89","author":"L McGhee","year":"2003","unstructured":"McGhee, L. et al. Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism. J. Cell. Biochem. 89, 1005\u20131018. https:\/\/doi.org\/10.1002\/jcb.10548 (2003).","journal-title":"J. Cell. Biochem."},{"key":"78167_CR54","doi-asserted-by":"publisher","first-page":"10338","DOI":"10.1128\/MCB.25.23.10338-10351.2005","volume":"25","author":"Z Duan","year":"2005","unstructured":"Duan, Z., Zarebski, A., Montoya-Durango, D., Grimes, H. L. & Horwitz, M. Gfi1 coordinates epigenetic repression of p21Cip\/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1. Mol. Cell. Biol. 25, 10338\u201310351. https:\/\/doi.org\/10.1128\/MCB.25.23.10338-10351.2005 (2005).","journal-title":"Mol. Cell. Biol."},{"key":"78167_CR55","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.molcel.2007.06.039","volume":"27","author":"S Saleque","year":"2007","unstructured":"Saleque, S., Kim, J., Rooke, H. M. & Orkin, S. H. Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol. Cell 27, 562\u2013572. https:\/\/doi.org\/10.1016\/j.molcel.2007.06.039 (2007).","journal-title":"Mol. Cell"},{"key":"78167_CR56","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1242\/dev.02372","volume":"133","author":"M Acar","year":"2006","unstructured":"Acar, M. et al. Senseless physically interacts with proneural proteins and functions as a transcriptional co-activator. Development 133, 1979\u20131989. https:\/\/doi.org\/10.1242\/dev.02372 (2006).","journal-title":"Development"},{"key":"78167_CR57","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44328","author":"HI Jen","year":"2019","unstructured":"Jen, H. I. et al. Transcriptomic and epigenetic regulation of hair cell regeneration in the mouse utricle and its potentiation by Atoh1. Elife https:\/\/doi.org\/10.7554\/eLife.44328 (2019).","journal-title":"Elife"},{"key":"78167_CR58","doi-asserted-by":"publisher","first-page":"9445","DOI":"10.1073\/pnas.94.17.9445","volume":"94","author":"M Xiang","year":"1997","unstructured":"Xiang, M. et al. Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development. Proc. Natl. Acad. Sci. U.S.A. 94, 9445\u20139450 (1997).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"78167_CR59","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/sj.gt.3302826","volume":"14","author":"F Venail","year":"2007","unstructured":"Venail, F. et al. Coxsackie adenovirus receptor and alpha nu beta3\/alpha nu beta5 integrins in adenovirus gene transfer of rat cochlea. Gene Ther. 14, 30\u201337 (2007).","journal-title":"Gene Ther."},{"key":"78167_CR60","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/nbt.3801","volume":"35","author":"B Pan","year":"2017","unstructured":"Pan, B. et al. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat. Biotechnol. 35, 264\u2013272. https:\/\/doi.org\/10.1038\/nbt.3801 (2017).","journal-title":"Nat. Biotechnol."},{"key":"78167_CR61","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1523\/JNEUROSCI.3088-12.2013","volume":"33","author":"MM Mellado Lagarde","year":"2013","unstructured":"Mellado Lagarde, M. M. et al. Selective ablation of pillar and deiters\u2019 cells severely affects cochlear postnatal development and hearing in mice. J. Neurosci. 33, 1564\u20131576. https:\/\/doi.org\/10.1523\/JNEUROSCI.3088-12.2013 (2013).","journal-title":"J. Neurosci."},{"key":"78167_CR62","doi-asserted-by":"publisher","first-page":"16919","DOI":"10.1073\/pnas.1408064111","volume":"111","author":"MM Mellado Lagarde","year":"2014","unstructured":"Mellado Lagarde, M. M. et al. Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse. Proc. Natl. Acad. Sci. U.S.A. 111, 16919\u201316924. https:\/\/doi.org\/10.1073\/pnas.1408064111 (2014).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"78167_CR63","doi-asserted-by":"publisher","first-page":"15093","DOI":"10.1523\/JNEUROSCI.1709-12.2012","volume":"32","author":"JS Golub","year":"2012","unstructured":"Golub, J. S. et al. Hair cell replacement in adult mouse utricles after targeted ablation of hair cells with diphtheria toxin. J. Neurosci. 32, 15093\u201315105. https:\/\/doi.org\/10.1523\/JNEUROSCI.1709-12.2012 (2012).","journal-title":"J. Neurosci."},{"key":"78167_CR64","doi-asserted-by":"publisher","first-page":"15050","DOI":"10.1523\/JNEUROSCI.2325-15.2015","volume":"35","author":"T Kaur","year":"2015","unstructured":"Kaur, T. et al. Fractalkine signaling regulates macrophage recruitment into the cochlea and promotes the survival of spiral ganglion neurons after selective hair cell lesion. J. Neurosci. 35, 15050\u201315061. https:\/\/doi.org\/10.1523\/JNEUROSCI.2325-15.2015 (2015).","journal-title":"J. Neurosci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78167-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78167-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78167-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:15:32Z","timestamp":1670372132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78167-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,8]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["78167"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-78167-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,8]]},"assertion":[{"value":"18 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 December 2020","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":"21397"}}