We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix-loop-helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons' fate into "hair cells", highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of "intraganglionic" HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

Department of Anatomy and Neurobiology The University of Tennessee Health Science Center Memphis TN 38163 USA

Department of Biology University of Iowa Iowa City IA 52242 USA

Department of Physiology and Cell Biology School of Medicine University of Nevada Reno NV 89557 USA

Institute of Biotechnology of the Czech Academy of Sciences 25250 Vestec Czechia

See more in PubMed

Fritzsch B., Pan N., Jahan I., Duncan J.S., Kopecky B.J., Elliott K.L., Kersigo J., Yang T. Evolution and development of the tetrapod auditory system: An organ of Corti-centric perspective. Evol. Dev. 2013;15:63–79. doi: 10.1111/ede.12015. PubMed DOI PMC

Luo Z.-X., Manley G.A. Origins and early evolution of mammalian ears and hearing function. In: Fritzsch B., editor. The Senses. Volume 2. Elsevier; Iowa City, NA, USA: 2021. pp. 207–252.

Grothe B., Carr C.E., Casseday J.H., Fritzsch B., Köppl C. Evolution of the Vertebrate Auditory System. Springer Science & Business Media; Berlin, Germany: 2004. The Evolution of Central Pathways and Their Neural Processing Patterns; pp. 289–359.

Grothe B. The Auditory System Function—An Integrative Perspective. In: Fritzsch B., editor. The Senses. Volume 2. Elsevier; Iowa City, NA, USA: 2021. pp. 1–17.

Zine A., Messat Y., Fritzsch B. A human induced pluripotent stem cell-based modular platform to challenge sensorineural hearing loss. Stem Cells. 2021 doi: 10.1002/stem.3346. PubMed DOI PMC

Yamoah E.N., Li M., Shah A., Elliott K.L., Cheah K., Xu P.-X., Phillips S., Young S.M., Jr., Eberl D.F., Fritzsch B. Using Sox2 to alleviate the hallmarks of age-related hearing loss. Ageing Res. Rev. 2020;59:101042. doi: 10.1016/j.arr.2020.101042. PubMed DOI PMC

Resnik J., Polley D.B. Cochlear neural degeneration disrupts hearing in background noise by increasing auditory cortex internal noise. Neuron. 2021;109:984–996.e4. doi: 10.1016/j.neuron.2021.01.015. PubMed DOI PMC

Kersigo J., Fritzsch B. Inner ear hair cells deteriorate in mice engineered to have no or diminished innervation. Front. Aging Neurosci. 2015;7:33. doi: 10.3389/fnagi.2015.00033. PubMed DOI PMC

Rubel E.W., Fritzsch B. Auditory system development: Primary auditory neurons and their targets. Annu. Rev. Neurosci. 2002;25:51–101. doi: 10.1146/annurev.neuro.25.112701.142849. PubMed DOI

De No R.L. The Primary Acoustic Nuclei. Raven Press; New York, NY, USA: 1981.

Ruben R.J. Development of the inner ear of the mouse: A radioautographic study of terminal mitoses. Acta Otolaryngol. 1967;220:1–44. PubMed

Matei V., Pauley S., Kaing S., Rowitch D., Beisel K., Morris K., Feng F., Jones K., Lee J., Fritzsch B. Smaller inner ear sensory epithelia in Neurog1 null mice are related to earlier hair cell cycle exit. Dev. Dyn. 2005;234:633–650. doi: 10.1002/dvdy.20551. PubMed DOI PMC

Pierce E.T. Histogenesis of the dorsal and ventral cochlear nuclei in the mouse. An autoradiographic study. J. Comp. Neurol. 1967;131:27–53. doi: 10.1002/cne.901310104. PubMed DOI

Fritzsch B., Elliott K.L., Pavlinkova G. Primary sensory map formations reflect unique needs and molecular cues specific to each sensory system. F1000Reseach. 2019;8 doi: 10.12688/f1000research.17717.1. PubMed DOI PMC

Ma Q., Anderson D.J., Fritzsch B. Neurogenin 1 null mutant ears develop fewer, morphologically normal hair cells in smaller sensory epithelia devoid of innervation. J. Assoc. Res. Otolaryngol. 2000;1:129–143. doi: 10.1007/s101620010017. PubMed DOI PMC

Kim W.-Y., Fritzsch B., Serls A., Bakel L.A., Huang E.J., Reichardt L.F., Barth D.S., Lee J.E. NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development. Development. 2001;128:417–426. PubMed PMC

Ma Q., Chen Z., del Barco Barrantes I., de la Pompa J.L., Anderson D.J. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron. 1998;20:469–482. doi: 10.1016/S0896-6273(00)80988-5. PubMed DOI

Liu M., Pereira F.A., Price S.D., Chu M.-j., Shope C., Himes D., Eatock R.A., Brownell W.E., Lysakowski A., Tsai M.-J. Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systems. Genes Dev. 2000;14:2839–2854. doi: 10.1101/gad.840500. PubMed DOI PMC

Zuo J., Treadaway J., Buckner T.W., Fritzsch B. Visualization of α9 acetylcholine receptor expression in hair cells of transgenic mice containing a modified bacterial artificial chromosome. Proc. Natl. Acad. Sci.USA. 1999;96:14100–14105. doi: 10.1073/pnas.96.24.14100. PubMed DOI PMC

Booth K.T., Azaiez H., Jahan I., Smith R.J., Fritzsch B. Intracellular Regulome Variability Along the Organ of Corti: Evidence, Approaches, Challenges, and Perspective. Front. Genet. 2018;9:156. doi: 10.3389/fgene.2018.00156. PubMed DOI PMC

Muniak M.A., Connelly C.J., Suthakar K., Milinkeviciute G., Ayeni F.E., Ryugo D.K. The Primary Auditory Neurons of the Mammalian Cochlea. Springer; New York, NY, USA: 2016. Central Projections of Spiral Ganglion Neurons; pp. 157–190.

Lowenheim H., Furness D.N., Kil J., Zinn C., Gultig K., Fero M.L., Frost D., Gummer A.W., Roberts J.M., Rubel E.W., et al. Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. Proc. Natl. Acad. Sci.USA. 1999;96:4084–4088. doi: 10.1073/pnas.96.7.4084. PubMed DOI PMC

Chen P., Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development. 1999;126:1581–1590. PubMed

Bermingham N.A., Hassan B.A., Price S.D., Vollrath M.A., Ben-Arie N., Eatock R.A., Bellen H.J., Lysakowski A., Zoghbi H.Y. Math1: An essential gene for the generation of inner ear hair cells. Science. 1999;284:1837–1841. doi: 10.1126/science.284.5421.1837. PubMed DOI

Chen P., Johnson J.E., Zoghbi H.Y., Segil N. The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development. 2002;129:2495–2505. PubMed

Fritzsch B., Beisel K.W., Bermingham N.A. Developmental evolutionary biology of the vertebrate ear: Conserving mechanoelectric transduction and developmental pathways in diverging morphologies. Neuroreport. 2000;11:R35–R44. doi: 10.1097/00001756-200011270-00013. PubMed DOI

Fritzsch B., Beisel K.W., Hansen L.A. The molecular basis of neurosensory cell formation in ear development: A blueprint for hair cell and sensory neuron regeneration? Bioessays. 2006;28:1181–1193. doi: 10.1002/bies.20502. PubMed DOI PMC

Jahan I., Pan N., Kersigo J., Fritzsch B. Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea. PLoS ONE. 2010;5:e11661. doi: 10.1371/journal.pone.0011661. PubMed DOI PMC

Fritzsch B., Eberl D.F., Beisel K.W. The role of bHLH genes in ear development and evolution: Revisiting a 10-year-old hypothesis. Cell. Mol. Life Sci. CMLS. 2010;67:3089–3099. doi: 10.1007/s00018-010-0403-x. PubMed DOI PMC

Fritzsch B., Dillard M., Lavado A., Harvey N.L., Jahan I. Canal cristae growth and fiber extension to the outer hair cells of the mouse ear require Prox1 activity. PLoS ONE. 2010;5:e9377. doi: 10.1371/journal.pone.0009377. PubMed DOI PMC

Kopecky B.J., Jahan I., Fritzsch B. Correct timing of proliferation and differentiation is necessary for normal inner ear development and auditory hair cell viability. Dev. Dyn. 2013;242:132–147. doi: 10.1002/dvdy.23910. PubMed DOI PMC

Kopecky B., Santi P., Johnson S., Schmitz H., Fritzsch B. Conditional deletion of N-Myc disrupts neurosensory and non-sensory development of the ear. Dev. Dyn. 2011;240:1373–1390. doi: 10.1002/dvdy.22620. PubMed DOI PMC

Wang V.Y., Rose M.F., Zoghbi H.Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron. 2005;48:31–43. doi: 10.1016/j.neuron.2005.08.024. PubMed DOI

Karis A., Pata I., van Doorninck J.H., Grosveld F., de Zeeuw C.I., de Caprona D., Fritzsch B. Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear. J. Comp. Neurol. 2001;429:615–630. doi: 10.1002/1096-9861(20010122)429:4<615::AID-CNE8>3.0.CO;2-F. PubMed DOI

Maklad A., Fritzsch B. Development of vestibular afferent projections into the hindbrain and their central targets. Brain Res. Bull. 2003;60:497–510. doi: 10.1016/S0361-9230(03)00054-6. PubMed DOI PMC

Jahan I., Kersigo J., Pan N., Fritzsch B. Neurod1 regulates survival and formation of connections in mouse ear and brain. Cell Tissue Res. 2010;341:95–110. doi: 10.1007/s00441-010-0984-6. PubMed DOI PMC

Fritzsch B., Pauley S., Feng F., Matei V., Nichols D. The molecular and developmental basis of the evolution of the vertebrate auditory system. Int. J. Comp. Psychol. 2006;19:1–25.

Pan N., Jahan I., Lee J.E., Fritzsch B. Defects in the cerebella of conditional Neurod1 null mice correlate with effective Tg (Atoh1-cre) recombination and granule cell requirements for Neurod1 for differentiation. Cell Tissue Res. 2009;337:407–428. doi: 10.1007/s00441-009-0826-6. PubMed DOI PMC

Fujiyama T., Yamada M., Terao M., Terashima T., Hioki H., Inoue Y.U., Inoue T., Masuyama N., Obata K., Yanagawa Y. Inhibitory and excitatory subtypes of cochlear nucleus neurons are defined by distinct bHLH transcription factors, Ptf1a and Atoh1. Development. 2009;136:2049–2058. doi: 10.1242/dev.033480. PubMed DOI

Mishima Y., Lindgren A.G., Chizhikov V.V., Johnson R.L., Millen K.J. Overlapping function of Lmx1a and Lmx1b in anterior hindbrain roof plate formation and cerebellar growth. J. Neurosci. 2009;29:11377–11384. doi: 10.1523/JNEUROSCI.0969-09.2009. PubMed DOI PMC

Koehler K.R., Nie J., Longworth-Mills E., Liu X.-P., Lee J., Holt J.R., Hashino E. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat. Biotechnol. 2017;35:583. doi: 10.1038/nbt.3840. PubMed DOI PMC

Macova I., Pysanenko K., Chumak T., Dvorakova M., Bohuslavova R., Syka J., Fritzsch B., Pavlinkova G. Neurod1 is essential for the primary tonotopic organization and related auditory information processing in the midbrain. J. Neurosci. 2019;39:984–1004. doi: 10.1523/JNEUROSCI.2557-18.2018. PubMed DOI PMC

Filova I., Dvorakova M., Bohuslavova R., Pavlinek A., Elliott K.L., Vochyanova S., Fritzsch B., Pavlinkova G. Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers. Mol. Neurobiol. 2020;57:5307–5323. doi: 10.1007/s12035-020-02092-0. PubMed DOI PMC

Jahan I., Elliott K.L., Fritzsch B. Understanding molecular evolution and development of the organ of Corti can provide clues for hearing restoration. Integr. Comp. Biol. 2018;58:351–365. doi: 10.1093/icb/icy019. PubMed DOI PMC

Li H.J., Ray S.K., Pan P., Haigh J., Fritzsch B., Leiter A.B. Intestinal Neurod1 expression impairs paneth cell differentiation and promotes enteroendocrine lineage specification. Sci. Rep. 2019;9:19489. doi: 10.1038/s41598-019-55292-7. PubMed DOI PMC

Yang T., Kersigo J., Jahan I., Pan N., Fritzsch B. The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti. Hear. Res. 2011;278:21–33. doi: 10.1016/j.heares.2011.03.002. PubMed DOI PMC

Fritzsch B., Kersigo J., Yang T., Jahan I., Pan N. The Primary Auditory Neurons of the Mammalian Cochlea. Springer; New York, NY, USA: 2016. Neurotrophic Factor Function during Ear Development: Expression Changes Define Critical Phases for Neuronal Viability; pp. 49–84.

Fariñas I., Jones K.R., Tessarollo L., Vigers A.J., Huang E., Kirstein M., De Caprona D.C., Coppola V., Backus C., Reichardt L.F. Spatial shaping of cochlear innervation by temporally regulated neurotrophin expression. J. Neurosci. 2001;21:6170–6180. doi: 10.1523/JNEUROSCI.21-16-06170.2001. PubMed DOI PMC

Fritzsch B., Silos-Santiago I., Bianchi L.M., Farinas I. The role of neurotrophic factors in regulating the development of inner ear innervation. Trends Neurosci. 1997;20:159–164. doi: 10.1016/S0166-2236(96)01007-7. PubMed DOI

Silos-Santiago I., Fagan A.M., Garber M., Fritzsch B., Barbacid M. Severe sensory deficits but normal CNS development in newborn mice lacking TrkB and TrkC tyrosine protein kinase receptors. Eur. J. Neurosci. 1997;9:2045–2056. doi: 10.1111/j.1460-9568.1997.tb01372.x. PubMed DOI

Coate T.M., Kelley M.W. Seminars in Cell & Developmental Biology. Volume 26. Academic Press; Cambridge, MA, USA: 2013. Making Connections in the Inner ear: Recent Insights into the Development of Spiral Ganglion Neurons and Their Connectivity with Sensory Hair Cells; pp. 460–469. PubMed PMC

Goodrich L.V. The Primary Auditory Neurons of the Mammalian Cochlea. Springer; New York, NY, USA: 2016. Early Development of the Spiral Ganglion; pp. 11–48.

Jung J.S., Zhang K.D., Wang Z., McMurray M., Tkaczuk A., Ogawa Y., Hertzano R., Coate T.M. Semaphorin-5B controls spiral ganglion neuron branch refinement during development. J. Neurosci. 2019;39:6425–6438. doi: 10.1523/JNEUROSCI.0113-19.2019. PubMed DOI PMC

Druckenbrod N., Hale E., Olukoya O., Shatzer W., Goodrich L. Neuronal processes and glial precursors form a scaffold for wiring the developing mouse cochlea. Nat. Commun. 2020;11:1–11. doi: 10.1038/s41467-020-19521-2. PubMed DOI PMC

Gu C., Rodriguez E.R., Reimert D.V., Shu T., Fritzsch B., Richards L.J., Kolodkin A.L., Ginty D.D. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell. 2003;5:45–57. doi: 10.1016/S1534-5807(03)00169-2. PubMed DOI PMC

Nishimura K., Noda T., Dabdoub A. Dynamic expression of Sox2, Gata3, and Prox1 during primary auditory neuron development in the mammalian cochlea. PLoS ONE. 2017;12:e0170568. doi: 10.1371/journal.pone.0170568. PubMed DOI PMC

Mao Y., Reiprich S., Wegner M., Fritzsch B. Targeted deletion of Sox10 by Wnt1-cre defects neuronal migration and projection in the mouse inner ear. PLoS ONE. 2014;9:e94580. doi: 10.1371/journal.pone.0094580. PubMed DOI PMC

Ghimire S.R., Deans M.R. Frizzled3 and Frizzled6 Cooperate with Vangl2 to Direct Cochlear Innervation by type II Spiral Ganglion Neurons. J. Neurosci. 2019;39:8013–8023. doi: 10.1523/JNEUROSCI.1740-19.2019. PubMed DOI PMC

Jahan I., Pan N., Kersigo J., Calisto L.E., Morris K.A., Kopecky B., Duncan J.S., Beisel K.W., Fritzsch B. Expression of Neurog1 instead of Atoh1 can partially rescue organ of Corti cell survival. PLoS ONE. 2012;7:e30853. doi: 10.1371/journal.pone.0030853. PubMed DOI PMC

Jahan I., Pan N., Kersigo J., Fritzsch B. Neurog1 can partially substitute for Atoh1 function in hair cell differentiation and maintenance during organ of Corti development. Development. 2015;142:2810–2821. doi: 10.1242/dev.123091. PubMed DOI PMC

Liberman M.C. Noise-induced and age-related hearing loss: New perspectives and potential therapies. F1000Reseach. 2017;6 doi: 10.12688/f1000research.11310.1. PubMed DOI PMC

Song Z., Jadali A., Fritzsch B., Kwan K.Y. NEUROG1 Regulates CDK2 to Promote Proliferation in Otic Progenitors. Stem Cell Rep. 2017;9:1516–1529. doi: 10.1016/j.stemcr.2017.09.011. PubMed DOI PMC

Xu J., Ueno H., Xu C.Y., Chen B., Weissman I.L., Xu P.X. Identification of mouse cochlear progenitors that develop hair and supporting cells in the organ of Corti. Nat Commun. 2017;8:15046. doi: 10.1038/ncomms15046. PubMed DOI PMC

Morris J.K., Maklad A., Hansen L.A., Feng F., Sorensen C., Lee K.-F., Macklin W.B., Fritzsch B. A disorganized innervation of the inner ear persists in the absence of ErbB2. Brain Res. 2006;1091:186–199. doi: 10.1016/j.brainres.2006.02.090. PubMed DOI PMC

Nakano Y., Jahan I., Bonde G., Sun X., Hildebrand M.S., Engelhardt J.F., Smith R.J., Cornell R.A., Fritzsch B., Bánfi B. A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse. PLoS Genet. 2012;8:e1002966. doi: 10.1371/journal.pgen.1002966. PubMed DOI PMC

Bouchard M., de Caprona D., Busslinger M., Xu P., Fritzsch B. Pax2 and Pax8 cooperate in mouse inner ear morphogenesis and innervation. BMC Dev. Biol. 2010;10:89. doi: 10.1186/1471-213X-10-89. PubMed DOI PMC

Chizhikov V.V., Iskusnykh I.Y., Fattakhov N., Fritzsch B. Lmx1a and Lmx1b are Redundantly Required for the Development of Multiple Components of the Mammalian Auditory System. Neuroscience. 2021;452:247–264. doi: 10.1016/j.neuroscience.2020.11.013. PubMed DOI PMC

Fritzsch B., Matei V., Nichols D., Bermingham N., Jones K., Beisel K., Wang V. Atoh1 null mice show directed afferent fiber growth to undifferentiated ear sensory epithelia followed by incomplete fiber retention. Dev. Dyn. Off. Publ. Am. Assoc. Anat. 2005;233:570–583. doi: 10.1002/dvdy.20370. PubMed DOI PMC

Nichols D.H., Pauley S., Jahan I., Beisel K.W., Millen K.J., Fritzsch B. Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis. Cell Tissue Res. 2008;334:339–358. doi: 10.1007/s00441-008-0709-2. PubMed DOI PMC

Xiang M., Maklad A., Pirvola U., Fritzsch B. Brn3c null mutant mice show long-term, incomplete retention of some afferent inner ear innervation. BMC Neurosci. 2003;4:2. doi: 10.1186/1471-2202-4-2. PubMed DOI PMC

Pauley S., Kopecky B., Beisel K., Soukup G., Fritzsch B. Stem cells and molecular strategies to restore hearing. Panminerva Med. 2008;50:41. PubMed PMC

Pan N., Jahan I., Kersigo J., Kopecky B., Santi P., Johnson S., Schmitz H., Fritzsch B. Conditional deletion of Atoh1 using Pax2-Cre results in viable mice without differentiated cochlear hair cells that have lost most of the organ of Corti. Hear. Res. 2011;275:66–80. doi: 10.1016/j.heares.2010.12.002. PubMed DOI PMC

Pan N., Jahan I., Kersigo J., Duncan J.S., Kopecky B., Fritzsch B. A novel Atoh1 “self-terminating” mouse model reveals the necessity of proper Atoh1 level and duration for hair cell differentiation and viability. PLoS ONE. 2012;7:e30358. doi: 10.1371/journal.pone.0030358. PubMed DOI PMC

Shibata S.B., Cortez S.R., Beyer L.A., Wiler J.A., Di Polo A., Pfingst B.E., Raphael Y. Transgenic BDNF induces nerve fiber regrowth into the auditory epithelium in deaf cochleae. Exp. Neurol. 2010;223:464–472. doi: 10.1016/j.expneurol.2010.01.011. PubMed DOI PMC

Puligilla C., Dabdoub A., Brenowitz S.D., Kelley M.W. Sox2 induces neuronal formation in the developing mammalian cochlea. J. Neurosci. 2010;30:714–722. doi: 10.1523/JNEUROSCI.3852-09.2010. PubMed DOI PMC

Steevens A.R., Sookiasian D.L., Glatzer J.C., Kiernan A.E. SOX2 is required for inner ear neurogenesis. Sci. Rep. 2017;7:4086. doi: 10.1038/s41598-017-04315-2. PubMed DOI PMC

Xu J., Li J., Zhang T., Jiang H., Ramakrishnan A., Fritzsch B., Shen L., Xu P.X. Chromatin remodelers and lineage-specific factors interact to target enhancers to establish proneurosensory fate within otic ectoderm. Proc. Natl. Acad. Sci.USA. 2021;118 doi: 10.1073/pnas.2025196118. PubMed DOI PMC

Dvorakova M., Macova I., Bohuslavova R., Anderova M., Fritzsch B., Pavlinkova G. Early ear neuronal development, but not olfactory or lens development, can proceed without SOX2. Dev. Biol. 2020;457:43–56. doi: 10.1016/j.ydbio.2019.09.003. PubMed DOI PMC

Dvorakova M., Jahan I., Macova I., Chumak T., Bohuslavova R., Syka J., Fritzsch B., Pavlinkova G. Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance. Sci. Rep. 2016;6:38253. doi: 10.1038/srep38253. PubMed DOI PMC

Kiernan A.E., Pelling A.L., Leung K.K., Tang A.S., Bell D.M., Tease C., Lovell-Badge R., Steel K.P., Cheah K.S. Sox2 is required for sensory organ development in the mammalian inner ear. Nature. 2005;434:1031. doi: 10.1038/nature03487. PubMed DOI

Zou D., Silvius D., Fritzsch B., Xu P.-X. Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development. 2004;131:5561–5572. doi: 10.1242/dev.01437. PubMed DOI PMC

Yang T., Kersigo J., Wu S., Fritzsch B., Bassuk A.G. Prickle1 regulates neurite outgrowth of apical spiral ganglion neurons but not hair cell polarity in the murine cochlea. PLoS ONE. 2017;12:e0183773. doi: 10.1371/journal.pone.0183773. PubMed DOI PMC

Duncan J.S., Fritzsch B. Continued expression of GATA3 is necessary for cochlear neurosensory development. PLoS ONE. 2013;8:e62046. doi: 10.1371/journal.pone.0062046. PubMed DOI PMC

Soukup G.A., Fritzsch B., Pierce M.L., Weston M.D., Jahan I., McManus M.T., Harfe B.D. Residual microRNA expression dictates the extent of inner ear development in conditional Dicer knockout mice. Dev. Biol. 2009;328:328–341. doi: 10.1016/j.ydbio.2009.01.037. PubMed DOI PMC

Kersigo J., D’Angelo A., Gray B.D., Soukup G.A., Fritzsch B. The role of sensory organs and the forebrain for the development of the craniofacial shape as revealed by Foxg1-cre-mediated microRNA loss. Genesis. 2011;49:326–341. doi: 10.1002/dvg.20714. PubMed DOI PMC

Lee Y.-S., Liu F., Segil N. A morphogenetic wave of p27Kip1 transcription directs cell cycle exit during organ of Corti development. Development. 2006;133:2817–2826. doi: 10.1242/dev.02453. PubMed DOI

Tateya T., Sakamoto S., Ishidate F., Hirashima T., Imayoshi I., Kageyama R. Three-dimensional live imaging of Atoh1 reveals the dynamics of hair cell induction and organization in the developing cochlea. Development. 2019;146 doi: 10.1242/dev.177881. PubMed DOI

Dabdoub A., Puligilla C., Jones J.M., Fritzsch B., Cheah K.S., Pevny L.H., Kelley M.W. Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea. Proc. Natl. Acad. Sci.USA. 2008;105:18396–18401. doi: 10.1073/pnas.0808175105. PubMed DOI PMC

Driver E.C., Sillers L., Coate T.M., Rose M.F., Kelley M.W. The Atoh1-lineage gives rise to hair cells and supporting cells within the mammalian cochlea. Dev. Biol. 2013;376:86–98. doi: 10.1016/j.ydbio.2013.01.005. PubMed DOI PMC

Driver E.C., Northrop A., Kelley M.W. Cell migration, intercalation and growth regulate mammalian cochlear extension. Development. 2017;144:3766–3776. doi: 10.1242/dev.151761. PubMed DOI PMC

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. 2013;33:10110–10122. doi: 10.1523/JNEUROSCI.5606-12.2013. PubMed DOI PMC

Chonko K.T., Jahan I., Stone J., Wright M.C., Fujiyama T., Hoshino M., Fritzsch B., Maricich S.M. Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. Dev. Biol. 2013;381:401–410. doi: 10.1016/j.ydbio.2013.06.022. PubMed DOI PMC

Kelly M.C., Chang Q., Pan A., Lin X., Chen P. Atoh1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. J. Neurosci. 2012;32:6699–6710. doi: 10.1523/JNEUROSCI.5420-11.2012. PubMed DOI PMC

White P.M., Doetzlhofer A., Lee Y.S., Groves A.K., Segil N. Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature. 2006;441:984. doi: 10.1038/nature04849. PubMed DOI

Nakano Y., Wiechert S., Fritzsch B., Bánfi B. Inhibition of a transcriptional repressor rescues hearing in a splicing factor-deficient mouse. Life Sci. Alliance. 2020;3 doi: 10.26508/lsa.202000841. PubMed DOI PMC

Dabdoub A., Nishimura K. Cochlear implants meet regenerative biology: State of the science and future research directions. Otol. Neurotol. 2017;38:e232–e236. doi: 10.1097/MAO.0000000000001407. PubMed DOI

Yamashita T., Zheng F., Finkelstein D., Kellard Z., Carter R., Rosencrance C.D., Sugino K., Easton J., Gawad C., Zuo J. High-resolution transcriptional dissection of in vivo Atoh1-mediated hair cell conversion in mature cochleae identifies Isl1 as a co-reprogramming factor. PLoS Genet. 2018;14:e1007552. doi: 10.1371/journal.pgen.1007552. PubMed DOI PMC

Walters B.J., Coak E., Dearman J., Bailey G., Yamashita T., Kuo B., Zuo J. In vivo interplay between p27Kip1, GATA3, ATOH1, and POU4F3 converts non-sensory cells to hair cells in adult mice. Cell Rep. 2017;19:307–320. doi: 10.1016/j.celrep.2017.03.044. PubMed DOI PMC

Lopez-Juarez A., Lahlou H., Ripoll C., Cazals Y., Brezun J.M., Wang Q., Edge A., Zine A. Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea. Mol. Ther. 2019;27:1101–1113. doi: 10.1016/j.ymthe.2019.03.018. PubMed DOI PMC

Lenz D.R., Gunewardene N., Abdul-Aziz D.E., Wang Q., Gibson T.M., Edge A.S. Applications of Lgr5-positive cochlear progenitors (LCPs) to the study of hair cell differentiation. Front. Cell Dev. Biol. 2019;7:14. doi: 10.3389/fcell.2019.00014. PubMed DOI PMC

Roccio M., Senn P., Heller S. Novel insights into inner ear development and regeneration for refined hearing loss therapies. Hear. Res. 2019;397:107859. PubMed

Zhang J., Wang Q., Abdul-Aziz D., Mattiacio J., Edge A.S., White P.M. ERBB 2 signaling drives supporting cell proliferation in vitro and apparent supernumerary hair cell formation in vivo in the neonatal mouse cochlea. Eur. J. Neurosci. 2018;48:3299–3316. doi: 10.1111/ejn.14183. PubMed DOI PMC

Schilder A.G., Su M.P., Blackshaw H., Lustig L., Staecker H., Lenarz T., Safieddine S., Gomes-Santos C.S., Holme R., Warnecke A. Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders. Otol. Neurotol. 2019;40:559–570. doi: 10.1097/MAO.0000000000002194. PubMed DOI

Iyer A.A., Groves A.K. Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells. Front. Cell. Neurosci. 2021;15 doi: 10.3389/fncel.2021.660748. PubMed DOI PMC

Krüger M., Schmid T., Krüger S., Bober E., Braun T. Functional redundancy of NSCL-1 and NeuroD during development of the petrosal and vestibulocochlear ganglia. Eur. J. Neurosci. 2006;24:1581–1590. doi: 10.1111/j.1460-9568.2006.05051.x. PubMed DOI

Jia S., Ivanov A., Blasevic D., Müller T., Purfürst B., Sun W., Chen W., Poy M.N., Rajewsky N., Birchmeier C. Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function. Embo. J. 2015;34:1417–1433. doi: 10.15252/embj.201490819. PubMed DOI PMC

Wiwatpanit T., Lorenzen S.M., Cantu J.A., Foo C.Z., Hogan A.K., Marquez F., Clancy J.C., Schipma M.J., Cheatham M.A., Duggan A., et al. Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature. 2018;563:691–695. doi: 10.1038/s41586-018-0570-8. PubMed DOI PMC

Lorenzen S.M., Duggan A., Osipovich A.B., Magnuson M.A., García-Añoveros J. Insm1 promotes neurogenic proliferation in delaminated otic progenitors. Mech. Dev. 2015;138:233–245. doi: 10.1016/j.mod.2015.11.001. PubMed DOI PMC

Wang V.Y., Hassan B.A., Bellen H.J., Zoghbi H.Y. Drosophila atonal fully rescues the phenotype of Math1 null mice: New functions evolve in new cellular contexts. Curr. Biol. 2002;12:1611–1616. doi: 10.1016/S0960-9822(02)01144-2. PubMed DOI

Fritzsch B., Elliott K.L. Gene, cell, and organ multiplication drives inner ear evolution. Dev. Biol. 2017;431:3–15. doi: 10.1016/j.ydbio.2017.08.034. PubMed DOI PMC

Jahan I., Pan N., Elliott K.L., Fritzsch B. The quest for restoring hearing: Understanding ear development more completely. Bioessays. 2015;37:1016–1027. doi: 10.1002/bies.201500044. PubMed DOI PMC

Fritzsch B., Elliott K.L. Auditory Nomenclature: Combining Name Recognition with Anatomical Description. Front. Neuroanat. 2018;12:99. doi: 10.3389/fnana.2018.00099. PubMed DOI PMC

Herranen A., Ikäheimo K., Lankinen T., Pakarinen E., Fritzsch B., Saarma M., Lindahl M., Pirvola U. Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss. Cell Death Dis. 2020;11:100. doi: 10.1038/s41419-020-2286-6. PubMed DOI PMC

Kempfle J.S., Turban J.L., Edge A.S. Sox2 in the differentiation of cochlear progenitor cells. Sci. Rep. 2016;6:23293. doi: 10.1038/srep23293. PubMed DOI PMC

Steevens A.R., Glatzer J.C., Kellogg C.C., Low W.C., Santi P.A., Kiernan A.E. SOX2 is required for inner ear growth and cochlear nonsensory formation before sensory development. Development. 2019;146:dev170522. doi: 10.1242/dev.170522. PubMed DOI PMC

Ahmed M., Xu J., Xu P.X. EYA1 and SIX1 drive the neuronal developmental program in cooperation with the SWI/SNF chromatin-remodeling complex and SOX2 in the mammalian inner ear. Development. 2012;139:1965–1977. doi: 10.1242/dev.071670. PubMed DOI PMC

Ahmed M., Wong E.Y., Sun J., Xu J., Wang F., Xu P.-X. Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Dev. Cell. 2012;22:377–390. doi: 10.1016/j.devcel.2011.12.006. PubMed DOI PMC

Kempfle J.S., Edge A.S. Pax2 and Sox2 Cooperate to Promote Hair Cell Fate in Inner Ear Stem Cells. Otolaryngol. Head Neck Surg. 2014;151:P221. doi: 10.1177/0194599814541629a266. DOI

Mann Z.F., Galvez H., Pedreno D., Chen Z., Chrysostomou E., Żak M., Kang M., Canden E., Daudet N. Shaping of inner ear sensory organs through antagonistic interactions between Notch signalling and Lmx1a. Elife. 2017;6:e33323. doi: 10.7554/eLife.33323. PubMed DOI PMC

Nichols D., Bouma J., Kopecky B., Jahan I., Beisel K.W., He D., Liu D., Fritzsch B. Interaction with ectopic cochlear crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice. Cell Tissue Res. 2020 doi: 10.1007/s00441-019-03163-y. in press. PubMed DOI PMC

Huang Y., Hill J., Yatteau A., Wong L., Jiang T., Petrovic J., Gan L., Dong L., Wu D.K. Reciprocal negative regulation between Lmx1a and Lmo4 is required for inner ear formation. J. Neurosci. 2018;38:5429–5440. doi: 10.1523/JNEUROSCI.2484-17.2018. PubMed DOI PMC

Pauley S., Lai E., Fritzsch B. Foxg1 is required for morphogenesis and histogenesis of the mammalian inner ear. Dev. Dyn. Off. Publ. Am. Assoc. Anat. 2006;235:2470–2482. doi: 10.1002/dvdy.20839. PubMed DOI PMC

Ding Y., Meng W., Kong W., He Z., Chai R. The Role of FoxG1 in the Inner Ear. Front. Cell Dev. Biol. 2020;8:1539. doi: 10.3389/fcell.2020.614954. PubMed DOI PMC

Pirvola U., Ylikoski J., Trokovic R., Hébert J.M., McConnell S.K., Partanen J. FGFR1 is required for the development of the auditory sensory epithelium. Neuron. 2002;35:671–680. doi: 10.1016/S0896-6273(02)00824-3. PubMed DOI

Roccio M., Perny M., Ealy M., Widmer H.R., Heller S., Senn P. Molecular characterization and prospective isolation of human fetal cochlear hair cell progenitors. Nat. Commun. 2018;9:4027. doi: 10.1038/s41467-018-06334-7. PubMed DOI PMC

Bermingham N.A., Hassan B.A., Wang V.Y., Fernandez M., Banfi S., Bellen H.J., Fritzsch B., Zoghbi H.Y. Proprioceptor pathway development is dependent on Math1. Neuron. 2001;30:411–422. doi: 10.1016/S0896-6273(01)00305-1. PubMed DOI

Ray R.S., Dymecki S.M. Rautenlippe Redux—toward a unified view of the precerebellar rhombic lip. Curr. Opin. Cell Biol. 2009;21:741–747. doi: 10.1016/j.ceb.2009.10.003. PubMed DOI PMC

Farago A.F., Awatramani R.B., Dymecki S.M. Assembly of the brainstem cochlear nuclear complex is revealed by intersectional and subtractive genetic fate maps. Neuron. 2006;50:205–218. doi: 10.1016/j.neuron.2006.03.014. PubMed DOI

Maricich S.M., Xia A., Mathes E.L., Wang V.Y., Oghalai J.S., Fritzsch B., Zoghbi H.Y. Atoh1-lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei. J. Neurosci. 2009;29:11123–11133. doi: 10.1523/JNEUROSCI.2232-09.2009. PubMed DOI PMC

Cai X., Kardon A.P., Snyder L.M., Kuzirian M.S., Minestro S., de Souza L., Rubio M.E., Maricich S.M., Ross S.E. Bhlhb5:: Flpo allele uncovers a requirement for Bhlhb5 for the development of the dorsal cochlear nucleus. Dev. Biol. 2016;414:149–160. doi: 10.1016/j.ydbio.2016.04.028. PubMed DOI PMC

Iskusnykh I.Y., Steshina E.Y., Chizhikov V.V. Loss of Ptf1a leads to a widespread cell-fate misspecification in the brainstem, affecting the development of somatosensory and viscerosensory nuclei. J. Neurosci. 2016;36:2691–2710. doi: 10.1523/JNEUROSCI.2526-15.2016. PubMed DOI PMC

Di Bonito M., Studer M., Puelles L. Nuclear derivatives and axonal projections originating from rhombomere 4 in the mouse hindbrain. Brain Struct. Funct. 2017;222:3509–3542. doi: 10.1007/s00429-017-1416-0. PubMed DOI PMC

Glover J.C., Elliott K.L., Erives A., Chizhikov V.V., Fritzsch B. Wilhelm His’ lasting insights into hindbrain and cranial ganglia development and evolution. Dev. Biol. 2018 doi: 10.1016/j.ydbio.2018.02.001. PubMed DOI PMC

Lunde A., Okaty B.W., Dymecki S.M., Glover J.C. Molecular profiling defines evolutionarily conserved transcription factor signatures of major vestibulospinal neuron groups. eNeuro. 2019;6 doi: 10.1523/ENEURO.0475-18.2019. PubMed DOI PMC

Elliott K.L., Kersigo J., Pan N., Jahan I., Fritzsch B. Spiral Ganglion Neuron Projection Development to the Hindbrain in Mice Lacking Peripheral and/or Central Target Differentiation. Front. Neural Circuits. 2017;11:25. doi: 10.3389/fncir.2017.00025. PubMed DOI PMC

Guillermo B. Ph.D. Thesis. Universitat Pompeu Fabra; Barcelona, Spain: 2019. Uncovering the Interplay between Call Fate Specification and Progenitor Dynamics during the Development of the Lower Rhombic Lip.

Hernandez-Miranda L.R., Müller T., Birchmeier C. The dorsal spinal cord and hindbrain: From developmental mechanisms to functional circuits. Dev. Biol. 2017;432:34–42. doi: 10.1016/j.ydbio.2016.10.008. PubMed DOI

Kersigo J., Gu L., Xu L., Pan N., Vijayakuma S., Jones T., Shibata S.B., Fritzsch B., Hansen M.R. Effects of Neurod1 Expression on Mouse and Human Schwannoma Cells. Laryngoscope. 2021;131:E259–E270. doi: 10.1002/lary.28671. PubMed DOI PMC

Lai H.C., Seal R.P., Johnson J.E. Making sense out of spinal cord somatosensory development. Development. 2016;143:3434–3448. doi: 10.1242/dev.139592. PubMed DOI PMC

Karmakar K., Narita Y., Fadok J., Ducret S., Loche A., Kitazawa T., Genoud C., Di Meglio T., Thierry R., Bacelo J. Hox2 genes are required for tonotopic map precision and sound discrimination in the mouse auditory brainstem. Cell Rep. 2017;18:185–197. doi: 10.1016/j.celrep.2016.12.021. PubMed DOI

Cheah K.S., Xu P.-X. Sox2. Elsevier; Amsterdam, The Netherlands: 2016. SOX2 in Neurosensory Fate Determination and Differentiation in the Inner Ear; pp. 263–280.

Kondoh H., Lovell-Badge R. Sox2: Biology and Role in Development and Disease. Academic Press; Cambridge, MA, USA: 2015.

Kageyama R., Shimojo H., Ohtsuka T. Dynamic control of neural stem cells by bHLH factors. Neurosci. Res. 2019;138:12–18. doi: 10.1016/j.neures.2018.09.005. PubMed DOI

Zhang T., Xu J., Xu P.X. Eya2 expression during mouse embryonic development revealed by Eya2 lacZ knockin reporter and homozygous mice show mild hearing loss. Dev. Dyn. :2021. doi: 10.1002/dvdy.326. PubMed DOI PMC

Duncan J.S., Fritzsch B., Houston D.W., Ketchum E.M., Kersigo J., Deans M.R., Elliott K.L. Topologically correct central projections of tetrapod inner ear afferents require Fzd3. Sci. Rep. 2019;9:10298. doi: 10.1038/s41598-019-46553-6. PubMed DOI PMC

Schmidt H., Fritzsch B. Npr2 null mutants show initial overshooting followed by reduction of spiral ganglion axon projections combined with near-normal cochleotopic projection. Cell Tissue Res. 2019;378:15–32. doi: 10.1007/s00441-019-03050-6. PubMed DOI PMC

Irx3/5 Null Deletion in Mice Blocks Cochlea-Saccule Segregation and Disrupts the Auditory Tonotopic Map

Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain

Single-cell RNA-sequencing analysis of the developing mouse inner ear identifies molecular logic of auditory neuron diversification

Early Deletion of Neurod1 Alters Neuronal Lineage Potential and Diminishes Neurogenesis in the Inner Ear