{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:25:54Z","timestamp":1786479954549,"version":"build-2736575974"},"reference-count":99,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DC015010"],"award-info":[{"award-number":["R01DC015010"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DC015444"],"award-info":[{"award-number":["R01DC015444"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000183","name":"United States Army Research Office","doi-asserted-by":"publisher","award":["USAMRMC-RH170030"],"award-info":[{"award-number":["USAMRMC-RH170030"]}],"id":[{"id":"10.13039\/100000183","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007254","name":"Creighton University","doi-asserted-by":"publisher","award":["LB692"],"award-info":[{"award-number":["LB692"]}],"id":[{"id":"10.13039\/100007254","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000006","name":"Office of Naval Research","doi-asserted-by":"publisher","award":["ONR-N00014-18-1-2507"],"award-info":[{"award-number":["ONR-N00014-18-1-2507"]}],"id":[{"id":"10.13039\/100000006","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Noise-induced, drug-related, and age-related disabling hearing loss is a major public health problem and affect approximately 466 million people worldwide. In non-mammalian vertebrates, the death of sensory hair cells (HCs) induces the proliferation and transdifferentiation of adjacent supporting cells into new HCs; however, this capacity is lost in juvenile and adult mammalian cochleae leading to permanent hearing loss. At present, cochlear implants and hearing devices are the only available treatments and can help patients to a certain extent; however, no biological approach or FDA-approved drug is effective to treat disabling hearing loss and restore hearing. Recently, regeneration of mammalian cochlear HCs by modulating molecular pathways or transcription factors has offered some promising results, although the immaturity of the regenerated HCs remains the biggest concern. Furthermore, most of the research done is in neonates and not in adults. This review focuses on critically summarizing the studies done in adult mammalian cochleae and discusses various strategies to elucidate novel transcription factors for better therapeutics.<\/jats:p>","DOI":"10.3390\/ijms23010066","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T10:24:52Z","timestamp":1640168692000},"page":"66","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Molecular Pathways Modulating Sensory Hair Cell Regeneration in Adult Mammalian Cochleae: Progress and Perspectives"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-2341","authenticated-orcid":false,"given":"Vikrant","family":"Rai","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Davis, A.C. (1983). Hearing disorders in the population: First phase findings of the MRC National Study of Hearing. Hearing Science and Hearing Disorders, Elsevier.","DOI":"10.1016\/B978-0-12-460440-7.50007-7"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1258\/ebm.2009.009281","article-title":"The challenge of hair cell regeneration","volume":"235","author":"Groves","year":"2010","journal-title":"Exp. Biol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1242\/dev.103036","article-title":"Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo","volume":"141","author":"Cox","year":"2014","journal-title":"Development"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1387\/ijdb.072408js","article-title":"Hair cell regeneration in the avian auditory epithelium","volume":"51","author":"Stone","year":"2007","journal-title":"Int. J. Dev. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.ymthe.2018.03.004","article-title":"Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs","volume":"26","author":"Du","year":"2018","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.celrep.2017.01.066","article-title":"Clonal expansion of Lgr5-positive cells from mammalian cochlea and high-purity generation of sensory hair cells","volume":"18","author":"McLean","year":"2017","journal-title":"Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"184","DOI":"10.3389\/fnmol.2019.00184","article-title":"Frizzled-9+ Supporting Cells Are Progenitors for the Generation of Hair Cells in the Postnatal Mouse Cochlea","volume":"12","author":"Zhang","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.celrep.2017.03.044","article-title":"In Vivo Interplay between p27(Kip1), GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice","volume":"19","author":"Walters","year":"2017","journal-title":"Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.neuron.2012.10.032","article-title":"Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma","volume":"77","author":"Mizutari","year":"2013","journal-title":"Neuron"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yamashita, T., Zheng, F., Finkelstein, D., Kellard, Z., Carter, R., Rosencrance, C.D., Sugino, K., Easton, J., Gawad, C., and Zuo, J. (2018). 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.","DOI":"10.1371\/journal.pgen.1007552"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-13157-7","article-title":"Renewed proliferation in adult mouse cochlea and regeneration of hair cells","volume":"10","author":"Shu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6600","DOI":"10.1523\/JNEUROSCI.0818-12.2012","article-title":"Age-dependent in vivo conversion of mouse cochlear pillar and Deiters\u2019 cells to immature hair cells by Atoh1 ectopic expression","volume":"32","author":"Liu","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0028-2243(88)90030-5","article-title":"Fetal hearing","volume":"28","author":"Querleu","year":"1988","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.conb.2008.10.001","article-title":"Hair cell regeneration","volume":"18","author":"Edge","year":"2008","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1242\/dev.119149","article-title":"Generation of sensory hair cells by genetic programming with a combination of transcription factors","volume":"142","author":"Costa","year":"2015","journal-title":"Development"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10786","DOI":"10.1523\/JNEUROSCI.0967-15.2015","article-title":"In vivo cochlear hair cell generation and survival by coactivation of \u03b2-catenin and Atoh1","volume":"35","author":"Kuo","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"66754","DOI":"10.18632\/oncotarget.11479","article-title":"Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea","volume":"7","author":"Ni","year":"2016","journal-title":"Oncotarget"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1242\/dev.114926","article-title":"Sensory hair cell development and regeneration: Similarities and differences","volume":"142","author":"Atkinson","year":"2015","journal-title":"Development"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7350","DOI":"10.1523\/JNEUROSCI.0312-08.2008","article-title":"Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans","volume":"28","author":"Driver","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3848","DOI":"10.1242\/dev.095398","article-title":"Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea","volume":"140","author":"Tateya","year":"2013","journal-title":"Development"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12865","DOI":"10.1523\/JNEUROSCI.1494-14.2014","article-title":"Hey1 and Hey2 control the spatial and temporal pattern of mammalian auditory hair cell differentiation downstream of Hedgehog signaling","volume":"34","author":"Doetzlhofer","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.gene.2014.12.054","article-title":"Control of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5","volume":"558","author":"Su","year":"2015","journal-title":"Gene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.heares.2016.12.011","article-title":"Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development?","volume":"349","author":"Zheng","year":"2017","journal-title":"Hear. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e44431","DOI":"10.7554\/eLife.44431","article-title":"scRNA-Seq reveals distinct stem cell populations that drive hair cell regeneration after loss of Fgf and Notch signaling","volume":"8","author":"Lush","year":"2019","journal-title":"Elife"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1242\/dev.02734","article-title":"Zebrafish atoh1 genes: Classic proneural activity in the inner ear and regulation by Fgf and Notch","volume":"134","author":"Millimaki","year":"2007","journal-title":"Development"},{"key":"ref_26","first-page":"156","article-title":"Atoh1 expression defines activated progenitors and differentiating hair cells during avian hair cell regeneration","volume":"236","author":"Cafaro","year":"2007","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1126\/science.284.5421.1837","article-title":"Math1: An essential gene for the generation of inner ear hair cells","volume":"284","author":"Bermingham","year":"1999","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Radosevic, M., Fargas, L., and Alsina, B. (2014). The role of her4 in inner ear development and its relationship with proneural genes and Notch signalling. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109860"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3764","DOI":"10.1242\/dev.074476","article-title":"Delta-like 1 and lateral inhibition during hair cell formation in the chicken inner ear: Evidence against cis-inhibition","volume":"139","author":"Chrysostomou","year":"2012","journal-title":"Development"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.heares.2018.01.004","article-title":"Transcriptomic analysis of chicken cochleae after gentamicin damage and the involvement of four signaling pathways (Notch, FGF, Wnt and BMP) in hair cell regeneration","volume":"361","author":"Jiang","year":"2018","journal-title":"Hear. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1523\/JNEUROSCI.2606-13.2014","article-title":"The transcriptome of utricle hair cell regeneration in the avian inner ear","volume":"34","author":"Ku","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4712","DOI":"10.1523\/JNEUROSCI.21-13-04712.2001","article-title":"Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear","volume":"21","author":"Zine","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1242\/dev.060657","article-title":"Jagged 1 regulates the restriction of Sox2 expression in the developing chicken inner ear: A mechanism for sensory organ specification","volume":"138","author":"Neves","year":"2011","journal-title":"Development"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: Single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.aanat.2019.07.001","article-title":"Wnt\/\u03b2-catenin signaling was activated in supporting cells during exposure of the zebrafish lateral line to cisplatin","volume":"226","author":"Mi","year":"2019","journal-title":"Ann. Anat.-Anat. Anz."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/dneu.22134","article-title":"The role of Wnt\/\u03b2-catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line","volume":"74","author":"Jacques","year":"2014","journal-title":"Dev. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0012-1606(03)00297-5","article-title":"Forced activation of Wnt signaling alters morphogenesis and sensory organ identity in the chicken inner ear","volume":"261","author":"Stevens","year":"2003","journal-title":"Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1242\/dev.045666","article-title":"Repression of Hedgehog signalling is required for the acquisition of dorsolateral cell fates in the zebrafish otic vesicle","volume":"137","author":"Hammond","year":"2010","journal-title":"Development"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3746","DOI":"10.1073\/pnas.1417856112","article-title":"Conserved role of Sonic Hedgehog in tonotopic organization of the avian basilar papilla and mammalian cochlea","volume":"112","author":"Son","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Maier, E.C., and Whitfield, T.T. (2014). RA and FGF signalling are required in the zebrafish otic vesicle to pattern and maintain ventral otic identities. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004858"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.heares.2012.04.018","article-title":"Fgf signaling regulates development and transdifferentiation of hair cells and supporting cells in the basilar papilla","volume":"289","author":"Jacques","year":"2012","journal-title":"Hear. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1006\/dbio.2001.0412","article-title":"FGFR3 expression during development and regeneration of the chick inner ear sensory epithelia","volume":"238","author":"Stone","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S0896-6273(02)00824-3","article-title":"FGFR1 is required for the development of the auditory sensory epithelium","volume":"35","author":"Pirvola","year":"2002","journal-title":"Neuron"},{"key":"ref_44","first-page":"1019","article-title":"Expression patterns of FGF receptors in the developing mammalian cochlea","volume":"239","author":"Hayashi","year":"2010","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9368","DOI":"10.1523\/JNEUROSCI.22-21-09368.2002","article-title":"Fibroblast growth factor signaling regulates pillar cell development in the organ of corti","volume":"22","author":"Mueller","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1242\/dev.02874","article-title":"Fgf8 induces pillar cell fate and regulates cellular patterning in the mammalian cochlea","volume":"134","author":"Jacques","year":"2007","journal-title":"Development"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5991","DOI":"10.1523\/JNEUROSCI.1690-08.2008","article-title":"Fgf20 is required for sensory epithelial specification in the developing cochlea","volume":"28","author":"Hayashi","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_48","first-page":"525","article-title":"Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti","volume":"236","author":"Hayashi","year":"2007","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"ref_49","first-page":"837","article-title":"Regulation of cell fate in the sensory epithelia of the inner ear. Nature reviews","volume":"7","author":"Kelley","year":"2006","journal-title":"Neuroscience"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3389\/fncel.2015.00110","article-title":"Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea","volume":"9","author":"Maass","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11621","DOI":"10.1038\/srep11621","article-title":"Sox2-CreER mice are useful for fate mapping of mature, but not neonatal, cochlear supporting cells in hair cell regeneration studies","volume":"5","author":"Walters","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3389\/fncel.2018.00120","article-title":"Spontaneous hair cell regeneration is prevented by increased notch signaling in supporting cells","volume":"12","author":"McGovern","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3389\/fncel.2015.00066","article-title":"Making sense of Wnt signaling\u2014linking hair cell regeneration to development","volume":"9","author":"Jansson","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8167","DOI":"10.1073\/pnas.1202774109","article-title":"Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea","volume":"109","author":"Chai","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"13851","DOI":"10.1073\/pnas.1219952110","article-title":"Generation of hair cells in neonatal mice by \u03b2-catenin overexpression in Lgr5-positive cochlear progenitors","volume":"110","author":"Shi","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1242\/dev.087528","article-title":"Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells","volume":"140","author":"Jan","year":"2013","journal-title":"Development"},{"key":"ref_57","first-page":"1","article-title":"Co-regulation of the Notch and Wnt signaling pathways promotes supporting cell proliferation and hair cell regeneration in mouse utricles","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1073\/pnas.1415901112","article-title":"Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway","volume":"112","author":"Li","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"8734","DOI":"10.1523\/JNEUROSCI.0060-16.2016","article-title":"Extensive supporting cell proliferation and mitotic hair cell generation by in vivo genetic reprogramming in the neonatal mouse cochlea","volume":"36","author":"Ni","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.devcel.2015.05.025","article-title":"Regeneration of sensory hair cells requires localized interactions between the Notch and Wnt pathways","volume":"34","author":"Acedo","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e55249","DOI":"10.7554\/eLife.55249","article-title":"Generation of inner ear hair cells by direct lineage conversion of primary somatic cells","volume":"9","author":"Menendez","year":"2020","journal-title":"eLife"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.2741\/4445","article-title":"Transcription factors in the development of inner ear hair cells","volume":"21","author":"Li","year":"2016","journal-title":"Front. Biosci."},{"key":"ref_63","first-page":"21","article-title":"Signaling and transcription factors during inner ear development: The generation of hair cells and otic neurons","volume":"5","author":"Giraldez","year":"2017","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neulet.2016.12.032","article-title":"Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter","volume":"652","author":"Venkatesh","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-50485-6","article-title":"Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors","volume":"9","author":"Dhara","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Begeman, I.J., and Kang, J. (2019). Transcriptional Programs and Regeneration Enhancers Underlying Heart Regeneration. J. Cardiovasc. Dev. Dis., 6.","DOI":"10.3390\/jcdd6010002"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ydbio.2008.07.004","article-title":"Prox1 interacts with Atoh1 and Gfi1, and regulates cellular differentiation in the inner ear sensory epithelia","volume":"322","author":"Kirjavainen","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.celrep.2019.06.028","article-title":"Atoh1 directs regeneration and functional recovery of the mature mouse vestibular system","volume":"28","author":"Sayyid","year":"2019","journal-title":"Cell Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ydbio.2013.06.022","article-title":"Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear","volume":"381","author":"Chonko","year":"2013","journal-title":"Dev. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s10162-015-0517-9","article-title":"A Sox10 rtTA\/+ Mouse Line Allows for Inducible Gene Expression in the Auditory and Balance Organs of the Inner Ear","volume":"16","author":"Walters","year":"2015","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6885","DOI":"10.1038\/srep06885","article-title":"Generation of Atoh1-rtTA transgenic mice: A tool for inducible gene expression in hair cells of the inner ear","volume":"4","author":"Cox","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/s41586-018-0570-8","article-title":"Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1","volume":"563","author":"Wiwatpanit","year":"2018","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41586-018-0728-4","article-title":"Helios is a key transcriptional regulator of outer hair cell maturation","volume":"563","author":"Chessum","year":"2018","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"759223","DOI":"10.3389\/fncel.2021.759223","article-title":"TUB and ZNF532 Promote the Atoh1-Mediated Hair Cell Regeneration in Mouse Cochleae","volume":"15","author":"Xu","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3389\/fnmol.2020.00013","article-title":"Characterizing Adult cochlear supporting cell transcriptional diversity using single-cell RNA-Seq: Validation in the adult mouse and translational implications for the adult human cochlea","volume":"13","author":"Hoa","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-019-1437-0","article-title":"Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea","volume":"10","author":"Cheng","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"dev171009","DOI":"10.1242\/dev.171009","article-title":"Multiple supporting cell subtypes are capable of spontaneous hair cell regeneration in the neonatal mouse cochlea","volume":"146","author":"McGovern","year":"2019","journal-title":"Development"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Liu, Z., Fang, J., Dearman, J., Zhang, L., and Zuo, J. (2014). In vivo generation of immature inner hair cells in neonatal mouse cochleae by ectopic Atoh1 expression. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089377"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"23293","DOI":"10.1038\/srep23293","article-title":"Sox2 in the differentiation of cochlear progenitor cells","volume":"6","author":"Kempfle","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5870","DOI":"10.1523\/JNEUROSCI.5083-14.2015","article-title":"Characterization of the transcriptome of nascent hair cells and identification of direct targets of the Atoh1 transcription factor","volume":"35","author":"Cai","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e44328","DOI":"10.7554\/eLife.44328","article-title":"Transcriptomic and epigenetic regulation of hair cell regeneration in the mouse utricle and its potentiation by Atoh1","volume":"8","author":"Jen","year":"2019","journal-title":"Elife"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Li, H. (2015). Epigenetic and Signaling Pathway Regulation in Hair Cell Regeneration, iMedPub LTD.","DOI":"10.21767\/2573-5365.100006"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3389\/fncel.2014.00446","article-title":"Epigenetic regulation in the inner ear and its potential roles in development, protection, and regeneration","volume":"8","author":"Layman","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.semcdb.2016.11.002","article-title":"Insights into inner ear-specific gene regulation: Epigenetics and non-coding RNAs in inner ear development and regeneration","volume":"65","author":"Doetzlhofer","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1242\/dev.137976","article-title":"Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea","volume":"143","author":"Stojanova","year":"2016","journal-title":"Development"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fncel.2016.00185","article-title":"Epigenetic DNA demethylation causes inner ear stem cell differentiation into hair cell-like cells","volume":"10","author":"Zhou","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/cddiscovery.2015.12","article-title":"Histone deacetylase inhibition protects hearing against acute ototoxicity by activating the Nf-\u03ba B pathway","volume":"1","author":"Layman","year":"2015","journal-title":"Cell Death Discov."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"D108","DOI":"10.1093\/nar\/gkj143","article-title":"TRANSFAC\u00ae and its module TRANSCompel\u00ae: Transcriptional gene regulation in eukaryotes","volume":"34","author":"Matys","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"D105","DOI":"10.1093\/nar\/gkp950","article-title":"JASPAR 2010: The greatly expanded open-access database of transcription factor binding profiles","volume":"38","author":"Thongjuea","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"D195","DOI":"10.1093\/nar\/gks1089","article-title":"HOCOMOCO: A comprehensive collection of human transcription factor binding sites models","volume":"41","author":"Kulakovskiy","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1016\/j.cell.2014.08.009","article-title":"Determination and inference of eukaryotic transcription factor sequence specificity","volume":"158","author":"Weirauch","year":"2014","journal-title":"Cell"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Janky, R., Verfaillie, A., Imrichova, H., Van de Sande, B., Standaert, L., Christiaens, V., Hulselmans, G., Herten, K., Naval Sanchez, M., and Potier, D. (2014). iRegulon: From a gene list to a gene regulatory network using large motif and track collections. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003731"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e66547","DOI":"10.7554\/eLife.66547","article-title":"Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells","volume":"10","author":"Sun","year":"2021","journal-title":"Elife"},{"key":"ref_94","first-page":"1689","article-title":"Basic helix\u2013loop\u2013helix gene Hes6 delineates the sensory hair cell lineage in the inner ear","volume":"235","author":"Qian","year":"2006","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1242\/dev.02567","article-title":"Characterization and function of the bHLH-O protein XHes2: Insight into the mechanisms controlling retinal cell fate decision","volume":"133","author":"Locker","year":"2006","journal-title":"Development"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1242\/dev.127.13.2933","article-title":"The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation","volume":"127","author":"Bae","year":"2000","journal-title":"Development"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1093\/hmg\/ddz010","article-title":"The TFAP2A\u2013IRF6\u2013GRHL3 genetic pathway is conserved in neurulation","volume":"28","author":"Kousa","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3288","DOI":"10.1073\/pnas.1100230108","article-title":"In vivo Atoh1 targetome reveals how a proneural transcription factor regulates cerebellar development","volume":"108","author":"Klisch","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.stem.2008.05.020","article-title":"Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development","volume":"3","author":"Kobayashi","year":"2008","journal-title":"Cell Stem Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/66\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:51:06Z","timestamp":1760169066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/66"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,22]]},"references-count":99,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23010066"],"URL":"https:\/\/doi.org\/10.3390\/ijms23010066","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,22]]}}}