We review the molecular basis of three related basic helix-loop-helix (bHLH) genes (Neurog1, Neurod1, and Atoh1) and upstream regulators Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires early expression of Neurog1, followed by its downstream target Neurod1, which downregulates Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 and Neurog1 expression for various aspects of development. Several experiments show a partial uncoupling of Atoh1/Neurod1 (spiral ganglia and cochlea) and Atoh1/Neurog1/Neurod1 (cochlear nuclei). In this review, we integrate the cellular and molecular mechanisms that regulate the development of auditory system and provide novel insights into the restoration of hearing loss, beyond the limited generation of lost sensory neurons and hair cells.

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 USA

Department of Physiology and Cell Biology University of Nevada Reno NV USA

Institute of Biotechnology of the Czech Academy of Sciences Vestec Czechia

Zobrazit více v PubMed

Dubno JR: New Insights on Age-Related Hearing Loss. J S C Acad Sci. 2019; 17: 3. Reference Source

Hoffman HJ, Dobie RA, Losonczy KG, et al. : Declining Prevalence of Hearing Loss in US Adults Aged 20 to 69 Years. JAMA Otolaryngol Head Neck Surg. 2017; 143(3): 274–85. 10.1001/jamaoto.2016.3527 PubMed DOI PMC

Liberman MC: Noise-induced and age-related hearing loss: new perspectives and potential therapies [version 1; peer review: 4 approved]. F1000Res. 2017; 6: 927. 10.12688/f1000research.11310.1 PubMed DOI PMC

Schilder AGM, Su MP, Blackshaw H, et al. : Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders. Otol Neurotol. 2019; 40(5): 559–70. 10.1097/MAO.0000000000002194 PubMed DOI

Yamoah EN, Li M, Shah A, et al. : Using Sox2 to alleviate the hallmarks of age-related hearing loss. Ageing Res Rev. 2020; 59: 101042. 10.1016/j.arr.2020.101042 PubMed DOI PMC

Lenz DR, Gunewardene N, Abdul-Aziz DE, et al. : Applications of Lgr5-Positive Cochlear Progenitors (LCPs) to the Study of Hair Cell Differentiation. Front Cell Dev Biol. 2019; 7: 14. 10.3389/fcell.2019.00014 PubMed DOI PMC

Roccio M, Perny M, Ealy M, et al. : Molecular characterization and prospective isolation of human fetal cochlear hair cell progenitors. Nat Commun. 2018; 9(1): 4027. 10.1038/s41467-018-06334-7 PubMed DOI PMC

Yamashita T, Zheng F, Finkelstein D, 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. 2018; 14(7): e1007552. 10.1371/journal.pgen.1007552 PubMed DOI PMC

Duncan JS, Cox BC: Anatomy and Development of the Inner Ear. In: Fritzsch, B. (Ed.), The senses. Elsevier, 2021; 253–275.

Jahan I, Elliott KL, Fritzsch B: Understanding Molecular Evolution and Development of the Organ of Corti Can Provide Clues for Hearing Restoration. Integr Comp Biol. 2018; 58(2): 351–65. 10.1093/icb/icy019 PubMed DOI PMC

Pan N, Jahan I, Kersigo J, et al. : 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(1): e30358. 10.1371/journal.pone.0030358 PubMed DOI PMC

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

Chizhikov VV, Iskusnykh IY, Fattakhov N, et al. : Lmx1a and Lmx1b are Redundantly Required for the Development of Multiple Components of the Mammalian Auditory System. Neuroscience. 2021; 452: 247–64. 10.1016/j.neuroscience.2020.11.013 PubMed DOI PMC

Glover JC, Elliott KL, Erives A, et al. : Wilhelm His' lasting insights into hindbrain and cranial ganglia development and evolution. Dev Biol. 2018; 444 Suppl 1(Suppl 1): S14–S24. 10.1016/j.ydbio.2018.02.001 PubMed DOI PMC

Lipovsek M, Wingate RJ: Conserved and divergent development of brainstem vestibular and auditory nuclei. eLife. 2018; 7: e40232. 10.7554/eLife.40232 PubMed DOI PMC

Macova I, Pysanenko K, Chumak T, et al. : Neurod1 Is Essential for the Primary Tonotopic Organization and Related Auditory Information Processing in the Midbrain. J Neurosci. 2019; 39(6): 984–1004. 10.1523/JNEUROSCI.2557-18.2018 PubMed DOI PMC

Maricich SM, Xia A, Mathes EL, et al. : 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(36): 11123–33. 10.1523/JNEUROSCI.2232-09.2009 PubMed DOI PMC

Nothwang HG: Evolution of mammalian sound localization circuits: A developmental perspective. Prog Neurobiol. 2016; 141: 1–24. 10.1016/j.pneurobio.2016.02.003 PubMed DOI

Ma Q, Anderson DJ, 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(2): 129–43. 10.1007/s101620010017 PubMed DOI PMC

Ma Q, Chen Z, Barrantes IdB, et al. : Neurogenin1 Is Essential for the Determination of Neuronal Precursors for Proximal Cranial Sensory Ganglia. Neuron. 1998; 20(3): 469–82. 10.1016/s0896-6273(00)80988-5 PubMed DOI

Guillermo B: Uncovering the interplay between call fate specification and progenitor dynamics during the development of the lower rhombic lip. Universitat Pompeu Fabra. 2019. Reference Source

Kim WY, Fritzsch B, Serls A, et al. : NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development. Development. 2001; 128(3): 417–26. PubMed PMC

Liu M, Pereira FA, Price SD, et al. : Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systems. Genes Dev. 2000; 14(22): 2839–54. 10.1101/gad.840500 PubMed DOI PMC

Bermingham NA, Hassan BA, Price SD, et al. : Math1: An essential gene for the generation of inner ear hair cells. Science. 1999; 284(5421): 1837–41. 10.1126/science.284.5421.1837 PubMed DOI

Mishima Y, Lindgren AG, Chizhikov VV, et al. : Overlapping function of Lmx1a and Lmx1b in anterior hindbrain roof plate formation and cerebellar growth. J Neurosci. 2009; 29(36): 11377–84. 10.1523/JNEUROSCI.0969-09.2009 PubMed DOI PMC

Wang VY, Rose MF, Zoghbi HY: Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron. 2005; 48(1): 31–43. 10.1016/j.neuron.2005.08.024 PubMed DOI

Filova I, Dvorakova M, Bohuslavova R, et al. : Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers. Mol Neurobiol. 2020; 57(12): 5307–23. 10.1007/s12035-020-02092-0 PubMed DOI PMC

Matei V, Pauley S, Kaing S, et al. : Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit. Dev Dyn. 2005; 234(3): 633–50. 10.1002/dvdy.20551 PubMed DOI PMC

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

Pierce ET: Histogenesis of the dorsal and ventral cochlear nuclei in the mouse. An autoradiographic study. J Comp Neurol. 1967; 131(1): 27–54. 10.1002/cne.901310104 PubMed DOI

Dvorakova M, Macova I, Bohuslavova R, et al. : Early ear neuronal development, but not olfactory or lens development, can proceed without SOX2. Dev Biol. 2020; 457(1): 43–56. 10.1016/j.ydbio.2019.09.003 PubMed DOI PMC

Goodrich LV: Early Development of the Spiral Ganglion. In: Dabdoub, A., Fritzsch, B., Popper, A.N., Fay, R.R. (Eds.), The Primary Auditory Neurons of the Mammalian Cochlea. Springer New York, New York, NY, 2016; 11–48. 10.1007/978-1-4939-3031-9_2 DOI

Groves AK, Fekete DM: Shaping sound in space: The regulation of inner ear patterning. Development. 2012; 139(2): 245–57. 10.1242/dev.067074 PubMed DOI PMC

Groves AK, Fekete DM: New Directions in Cochlear Development. Understanding the Cochlea. Springer, 2017; 33–73. 10.1007/978-3-319-52073-5_3 DOI

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(1): 15–32. 10.1007/s00441-019-03050-6 PubMed DOI PMC

Yang T, Kersigo J, Jahan I, et al. : The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti. Hear Res. 2011; 278(1–2): 21–33. 10.1016/j.heares.2011.03.002 PubMed DOI PMC

Maklad A, Kamel S, Wong E, et al. : Development and organization of polarity-specific segregation of primary vestibular afferent fibers in mice. Cell Tissue Res. 2010; 340(2): 303–21. 10.1007/s00441-010-0944-1 PubMed DOI PMC

Fujiyama T, Yamada M, Terao M, et al. : Inhibitory and excitatory subtypes of cochlear nucleus neurons are defined by distinct bHLH transcription factors, Ptf1a and Atoh1. Development. 2009; 136(12): 2049–58. 10.1242/dev.033480 PubMed DOI

Iskusnykh IY, Steshina EY, Chizhikov VV: 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(9): 2691–710. 10.1523/JNEUROSCI.2526-15.2016 PubMed DOI PMC

Raft S, Groves AK: Segregating neural and mechanosensory fates in the developing ear: Patterning, signaling, and transcriptional control. Cell Tissue Res. 2015; 359(1): 315–32. 10.1007/s00441-014-1917-6 PubMed DOI PMC

Pan N, Jahan I, Lee JE, et al. : 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(3): 407–28. 10.1007/s00441-009-0826-6 PubMed DOI PMC

Karis A, Pata I, van Doorninck JH, et al. : Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear. J Comp Neurol. 2001; 429(4): 615–30. 10.1002/1096-9861(20010122)429:4<615::aid-cne8>3.0.co;2-f PubMed DOI

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

Ahmed M, Wong EYM, Sun J, et al. : 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(2): 377–90. 10.1016/j.devcel.2011.12.006 PubMed DOI PMC

Pauley S, Lai E, Fritzsch B: Foxg1 is required for morphogenesis and histogenesis of the mammalian inner ear. Dev Dyn. 2006; 235(9): 2470–82. 10.1002/dvdy.20839 PubMed DOI PMC

Zhang S, Zhang Y, Dong Y, et al. : Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea. Cell Mol Life Sci. 2020; 77(7): 1401–19. 10.1007/s00018-019-03291-2 PubMed DOI PMC

Huang Y, Hill J, Yatteau A, et al. : Reciprocal Negative Regulation Between Lmx1a and Lmo4 Is Required for Inner Ear Formation. J Neurosci. 2018; 38(23): 5429–40. 10.1523/JNEUROSCI.2484-17.2018 PubMed DOI PMC

Mann ZF, Gálvez H, Pedreno D, et al. : Shaping of inner ear sensory organs through antagonistic interactions between Notch signalling and Lmx1a. eLife. 2017; 6: e33323. 10.7554/eLife.33323 PubMed DOI PMC

Nichols DH, Pauley S, Jahan I, et al. : Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis. Cell Tissue Res. 2008; 334(3): 339–58. 10.1007/s00441-008-0709-2 PubMed DOI PMC

Ahmed M, Xu J, Xu PX: 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(11): 1965–77. 10.1242/dev.071670 PubMed DOI PMC

Kempfle JS, Edge AS: Pax2 and Sox2 Cooperate to Promote Hair Cell Fate in Inner Ear Stem Cells. Otolaryngol Head Neck Surg. 2014; 151(1_suppl): P221–P221. 10.1177/0194599814541629a266 DOI

Kiernan AE, Pelling AL, Leung KKH, et al. : Sox2 is required for sensory organ development in the mammalian inner ear. Nature. 2005; 434(7036): 1031–5. 10.1038/nature03487 PubMed DOI

Li J, Zhang T, Ramakrishnan A, et al. : Dynamic changes in cis-regulatory occupancy by Six1 and its cooperative interactions with distinct cofactors drive lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium. Nucleic Acids Res. 2020; 48(6): 2880–96. 10.1093/nar/gkaa012 PubMed DOI PMC

Jahan I, Pan N, Kersigo J, et al. : Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea. PLoS One. 2010; 5(7): e11661. 10.1371/journal.pone.0011661 PubMed DOI PMC

Herranen A, Ikäheimo K, Lankinen T, et al. : Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss. Cell Death Dis. 2020; 11(2): 100. 10.1038/s41419-020-2286-6 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. 10.3389/fnagi.2015.00033 PubMed DOI PMC

Schimmang T, Pirvola U: Coupling the cell cycle to development and regeneration of the inner ear. Semin Cell Dev Biol. 2013; 24(5): 507–13. 10.1016/j.semcdb.2013.04.004 PubMed DOI

Fritzsch B, Matei VA, Nichols DH, et al. : Atoh1 null mice show directed afferent fiber growth to undifferentiated ear sensory epithelia followed by incomplete fiber retention. Dev Dyn. 2005; 233(2): 570–83. 10.1002/dvdy.20370 PubMed DOI PMC

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

Nakano Y, Jahan I, Bonde G, et al. : A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse. PLoS Genet. 2012; 8(10): e1002966. 10.1371/journal.pgen.1002966 PubMed DOI PMC

Nakano Y, Wiechert S, Fritzsch B, et al. : Inhibition of a transcriptional repressor rescues hearing in a splicing factor-deficient mouse. Life Sci. Alliance. 2020; 3(12): e202000841. 10.26508/lsa.202000841 PubMed DOI PMC

Jahan I, Pan N, Kersigo J, et al. : Expression of Neurog1 instead of Atoh1 can partially rescue organ of Corti cell survival. PLoS One. 2012; 7(1): e30853. 10.1371/journal.pone.0030853 PubMed DOI PMC

Jahan I, Pan N, Kersigo J, et al. : Neurog1 can partially substitute for Atoh1 function in hair cell differentiation and maintenance during organ of Corti development. Development. 2015; 142(16): 2810–21. 10.1242/dev.123091 PubMed DOI PMC

Booth KT, Azaiez H, Jahan I, et al. : Intracellular Regulome Variability Along the Organ of Corti: Evidence, Approaches, Challenges, and Perspective. Front Genet. 2018; 9: 156. 10.3389/fgene.2018.00156 PubMed DOI PMC

Daudet N, Żak M: Notch Signalling: The Multitask Manager of Inner Ear Development and Regeneration. Adv Exp Med Biol. 2020; 1218: 129–57. 10.1007/978-3-030-34436-8_8 PubMed DOI

Gnedeva K, Wang X, McGovern MM, et al. : Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal. Proc Natl Acad Sci U S A. 2020; 117(24): 13552–61. 10.1073/pnas.2000175117 PubMed DOI PMC

Xu J, Ueno H, Xu CY, et al. : Identification of mouse cochlear progenitors that develop hair and supporting cells in the organ of Corti. Nat Commun. 2017; 8: 15046. 10.1038/ncomms15046 PubMed DOI PMC

Song Z, Jadali A, Fritzsch B, et al. : NEUROG1 Regulates CDK2 to Promote Proliferation in Otic Progenitors. Stem Cell Reports. 2017; 9(5): 1516–29. 10.1016/j.stemcr.2017.09.011 PubMed DOI PMC

Song Z, Laureano AS, Patel K, et al. : Single-Cell Fluorescence Analysis of Pseudotemporal Ordered Cells Provides Protein Expression Dynamics for Neuronal Differentiation. Front Cell Dev Biol. 2019; 7: 87. 10.3389/fcell.2019.00087 PubMed DOI PMC

Liu MH, Li W, Zheng JJ, et al. : Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter. Neural Regen Res. 2020; 15(2): 342–51. 10.4103/1673-5374.265185 PubMed DOI PMC

Liu F, Zhang Y, Chen F, et al. : Neurog2 directly converts astrocytes into functional neurons in midbrain and spinal cord. Cell Death Dis. 2021; 12(3): 225. 10.1038/s41419-021-03498-x PubMed DOI PMC

Roccio M, Senn P, Heller S: Novel insights into inner ear development and regeneration for targeted hearing loss therapies. Hear Res. 2020; 397: 107859. 10.1016/j.heares.2019.107859 PubMed DOI

Dvorakova M, Jahan I, Macova I, et al. : Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance. Sci Rep. 2016; 6: 38253. 10.1038/srep38253 PubMed DOI PMC

Radde-Gallwitz K, Pan L, Gan L, et al. : Expression of Islet1 marks the sensory and neuronal lineages in the mammalian inner ear. J Comp Neurol. 2004; 477(4): 412–21. 10.1002/cne.20257 PubMed DOI PMC

Duncan JS, Fritzsch B: Continued expression of GATA3 is necessary for cochlear neurosensory development. PLoS One. 2013; 8(4): e62046. 10.1371/journal.pone.0062046 PubMed DOI PMC

Walters BJ, Coak E, Dearman J, et al. : In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice. Cell Rep. 2017; 19(2): 307–20. 10.1016/j.celrep.2017.03.044 PubMed DOI PMC

Lopez-Juarez A, Lahlou H, Ripoll C, et al. : Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea. Mol Ther. 2019; 27(6): 1101–13. 10.1016/j.ymthe.2019.03.018 PubMed DOI PMC

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

Shibata SB, Cortez SR, Beyer LA, et al. : Transgenic BDNF induces nerve fiber regrowth into the auditory epithelium in deaf cochleae. Exp Neurol. 2010; 223(2): 464–72. 10.1016/j.expneurol.2010.01.011 PubMed DOI PMC

Puligilla C, Dabdoub A, Brenowitz SD, et al. : Sox2 induces neuronal formation in the developing mammalian cochlea. J Neurosci. 2010; 30(2): 714–22. 10.1523/JNEUROSCI.3852-09.2010 PubMed DOI PMC

Steevens AR, Sookiasian DL, Glatzer JC, et al. : SOX2 is required for inner ear neurogenesis. Sci Rep. 2017; 7(1): 4086. 10.1038/s41598-017-04315-2 PubMed DOI PMC

Xu J, Li J, Zhang T, et al. : Chromatin remodelers and lineage-specific factors interact to target enhancers to establish proneurosensory fate within otic ectoderm. Proc Natl Acad Sci U S A. 2021; 118(12): e2025196118. 10.1073/pnas.2025196118 PubMed DOI PMC

Coate TM, Kelley MW: Making connections in the inner ear: Recent insights into the development of spiral ganglion neurons and their connectivity with sensory hair cells. Semin Cell Dev Biol. 2013; 24(5): 460–9. 10.1016/j.semcdb.2013.04.003 PubMed DOI PMC

Fritzsch B, Dillard M, Lavado A, et al. : Canal cristae growth and fiber extension to the outer hair cells of the mouse ear require Prox1 activity. PLoS One. 2010; 5(2): e9377. 10.1371/journal.pone.0009377 PubMed DOI PMC

Ghimire SR, Deans MR: Frizzled3 and Frizzled6 Cooperate with Vangl2 to Direct Cochlear Innervation by Type II Spiral Ganglion Neurons. J Neurosci. 2019; 39(41): 8013–23. 10.1523/JNEUROSCI.1740-19.2019 PubMed DOI PMC

Yang T, Kersigo J, Wu S, et al. : Prickle1 regulates neurite outgrowth of apical spiral ganglion neurons but not hair cell polarity in the murine cochlea. PLoS One. 2017; 12(8): e0183773. 10.1371/journal.pone.0183773 PubMed DOI PMC

Mao Y, Reiprich S, Wegner M, et al. : Targeted deletion of Sox10 by Wnt1-cre defects neuronal migration and projection in the mouse inner ear. PLoS One. 2014; 9(4): e94580. 10.1371/journal.pone.0094580 PubMed DOI PMC

Driver EC, Northrop A, Kelley MW: Cell migration, intercalation and growth regulate mammalian cochlear extension. Development. 2017; 144(20): 3766–76. 10.1242/dev.151761 PubMed DOI PMC

Soukup GA, Fritzsch B, Pierce ML, et al. : Residual microRNA expression dictates the extent of inner ear development in conditional Dicer knockout mice. Dev Biol. 2009; 328(2): 328–41. 10.1016/j.ydbio.2009.01.037 PubMed DOI PMC

Fritzsch B, Elliott KL: Gene, cell, and organ multiplication drives inner ear evolution. Dev Biol. 2017; 431(1): 3–15. 10.1016/j.ydbio.2017.08.034 PubMed DOI PMC

Fritzsch B, Pauley S, Feng F, et al. : The molecular and developmental basis of the evolution of the vertebrate auditory system. International Journal of Comparative Psychology. 2006; 19(1): 1–25. Reference Source

Gálvez H, Abelló G, Giraldez F: Signaling and Transcription Factors during Inner Ear Development: The Generation of Hair Cells and Otic Neurons. Front Cell Dev Biol. 2017; 5: 21. 10.3389/fcell.2017.00021 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(8): 3509–42. 10.1007/s00429-017-1416-0 PubMed DOI PMC

Hernandez-Miranda LR, Müller T, Birchmeier C: The dorsal spinal cord and hindbrain: From developmental mechanisms to functional circuits. Dev Biol. 2017; 432(1): 34–42. 10.1016/j.ydbio.2016.10.008 PubMed DOI

Bermingham NA, Hassan BA, Wang VY, et al. : Proprioceptor Pathway Development Is Dependent on MATH1. Neuron. 2001; 30(2): 411–22. 10.1016/s0896-6273(01)00305-1 PubMed DOI

Ray RS, Dymecki SM: Rautenlippe Redux -- toward a unified view of the precerebellar rhombic lip. Curr Opin Cell Biol. 2009; 21(6): 741–7. 10.1016/j.ceb.2009.10.003 PubMed DOI PMC

Cai X, Kardon AP, Snyder LM, et al. : Bhlhb5::flpo allele uncovers a requirement for Bhlhb5 for the development of the dorsal cochlear nucleus. Dev Biol. 2016; 414(2): 149–60. 10.1016/j.ydbio.2016.04.028 PubMed DOI PMC

Kersigo J, Gu L, Xu L, et al. : Effects of Neurod1 Expression on Mouse and Human Schwannoma Cells. Laryngoscope. 2021; 131(1): E259–E270. 10.1002/lary.28671 PubMed DOI PMC

Li HJ, Ray SK, Pan N, et al. : Intestinal Neurod1 expression impairs paneth cell differentiation and promotes enteroendocrine lineage specification. Sci Rep. 2019; 9(1): 19489. 10.1038/s41598-019-55292-7 PubMed DOI PMC

Cai T, Seymour ML, Zhang H, et al. : Conditional deletion of Atoh1 reveals distinct critical periods for survival and function of hair cells in the organ of Corti. J Neurosci. 2013; 33(24): 10110–22. 10.1523/JNEUROSCI.5606-12.2013 PubMed DOI PMC

Dennis DJ, Han S, Schuurmans C: bHLH transcription factors in neural development, disease, and reprogramming. Brain Res. 2019; 1705: 48–65. 10.1016/j.brainres.2018.03.013 PubMed DOI

Lunde A, Okaty BW, Dymecki SM, et al. : Molecular Profiling Defines Evolutionarily Conserved Transcription Factor Signatures of Major Vestibulospinal Neuron Groups. eNeuro. 2019; 6(1): ENEURO.0475-18.2019. 10.1523/ENEURO.0475-18.2019 PubMed DOI PMC

Karmakar K, Narita Y, Fadok J, et al. : Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem. Cell Rep. 2017; 18(1): 185–197. 10.1016/j.celrep.2016.12.021 PubMed DOI

Elliott KL, Kersigo J, Pan N, et al. : Spiral Ganglion Neuron Projection Development to the Hindbrain in Mice Lacking Peripheral and/or Central Target Differentiation. Front Neural Circuits. 2017; 11: 25. 10.3389/fncir.2017.00025 PubMed DOI PMC

Miyata T, Maeda T, Lee JE: NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev. 1999; 13(13): 1647–52. 10.1101/gad.13.13.1647 PubMed DOI PMC

Chen YC, Ma NX, Pei ZF, et al. : A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion. Mol Ther. 2020; 28(1): 217–234. 10.1016/j.ymthe.2019.09.003 PubMed DOI PMC

Ge LJ, Yang FH, Li W, et al. : In vivo Neuroregeneration to Treat Ischemic Stroke Through NeuroD1 AAV-Based Gene Therapy in Adult Non-human Primates. Front Cell Dev Biol. 2020; 8: 590008. 10.3389/fcell.2020.590008 PubMed DOI PMC

Ryugo DK, Kretzmer EA, Niparko JK: Restoration of auditory nerve synapses in cats by cochlear implants. Science. 2005; 310(5753): 1490–2. 10.1126/science.1119419 PubMed DOI

Cheah KSE, Xu PX: SOX2 in Neurosensory Fate Determination and Differentiation in the Inner Ear. Sox2. Elsevier, 2016; 263–280. 10.1016/B978-0-12-800352-7.00015-3 DOI

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

Duncan JS, Fritzsch B, Houston DW, et al. : Topologically correct central projections of tetrapod inner ear afferents require Fzd3. Sci Rep. 2019; 9(1): 10298. 10.1038/s41598-019-46553-6 PubMed DOI PMC

Chen P, Johnson JE, Zoghbi HY, et al. : The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development. 2002; 129(10): 2495–505. 10.1242/dev.129.10.2495 PubMed DOI

Menendez L, Trecek T, Gopalakrishnan S, et al. : Generation of inner ear hair cells by direct lineage conversion of primary somatic cells. eLife. 2020; 9: e55249. 10.7554/eLife.55249 PubMed DOI PMC

Driver EC, Sillers L, Coate TM, et al. : The Atoh1-lineage gives rise to hair cells and supporting cells within the mammalian cochlea. Dev Biol. 2013; 376(1): 86–98. 10.1016/j.ydbio.2013.01.005 PubMed DOI PMC

Lee YS, Liu F, Segil N: A morphogenetic wave of p27Kip1 transcription directs cell cycle exit during organ of Corti development. Development. 2006; 133(15): 2817–26. 10.1242/dev.02453 PubMed DOI

Kopecky BJ, 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(2): 132–47. 10.1002/dvdy.23910 PubMed DOI PMC

Tateya T, Sakamoto S, Ishidate F, et al. : Three-dimensional live imaging of Atoh1 reveals the dynamics of hair cell induction and organization in the developing cochlea. Development. 2019; 146(21): dev177881. 10.1242/dev.177881 PubMed DOI

Zuo J, Treadaway J, Buckner TW, et al. : Visualization of alpha9 acetylcholine receptor expression in hair cells of transgenic mice containing a modified bacterial artificial chromosome. Proc Natl Acad Sci U S A. 1999; 96(24): 14100–5. 10.1073/pnas.96.24.14100 PubMed DOI PMC

Kempfle JS, Nguyen K, Hamadani C, et al. : Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss. Bioconjug Chem. 2018; 29(4): 1240–1250. 10.1021/acs.bioconjchem.8b00022 PubMed DOI PMC

McLean WJ, Yin X, Lu L, et al. : Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Rep. 2017; 18(8): 1917–1929. 10.1016/j.celrep.2017.01.066 PubMed DOI PMC

Raft S, Koundakjian EJ, Quinones H, et al. : Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development. Development. 2007; 134(24): 4405–15. 10.1242/dev.009118 PubMed DOI

Liu Z, Owen T, Zhang L, et al. : Dynamic expression pattern of Sonic hedgehog in developing cochlear spiral ganglion neurons. Dev Dyn. 2010; 239(6): 1674–83. 10.1002/dvdy.22302 PubMed DOI PMC

Riccomagno MM, Takada S, Epstein DJ: Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes Dev. 2005; 19(13): 1612–23. 10.1101/gad.1303905 PubMed DOI PMC

Hwang CH, Simeone A, Lai E, et al. : Foxg1 is required for proper separation and formation of sensory cristae during inner ear development. Dev Dyn. 2009; 238(11): 2725–34. 10.1002/dvdy.22111 PubMed DOI

Chonko KT, Jahan I, Stone J, et al. : Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. Dev Biol. 2013; 381(2): 401–10. 10.1016/j.ydbio.2013.06.022 PubMed DOI PMC

Kelly MC, Chang Q, Pan A, et al. : Atoh1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. J Neurosci. 2012; 32(19): 6699–710. 10.1523/JNEUROSCI.5420-11.2012 PubMed DOI PMC

White PM, Doetzlhofer A, Lee YS, et al. : Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature. 2006; 441(7096): 984–7. 10.1038/nature04849 PubMed DOI

Zhang J, Wang Q, Abdul-Aziz D, et al. : ERBB2 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(10): 3299–316. 10.1111/ejn.14183 PubMed DOI PMC

Dabdoub A, Nishimura K: Cochlear Implants Meet Regenerative Biology: State of the Science and Future Research Directions. Otol Neurotol. 2017; 38(8): e232–e236. 10.1097/MAO.0000000000001407 PubMed DOI

Samarajeewa A, Jacques BE, Dabdoub A: Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration. Mol Ther. 2019; 27(5): 904–11. 10.1016/j.ymthe.2019.03.017 PubMed DOI PMC

Kempfle JS, Turban JL, Edge ASB: Sox2 in the differentiation of cochlear progenitor cells. Sci Rep. 2016; 6: 23293. 10.1038/srep23293 PubMed DOI PMC

Steevens AR, Glatzer JC, Kellogg CC, et al. : SOX2 is required for inner ear growth and cochlear nonsensory formation before sensory development. Development. 2019; 146(13): dev170522. 10.1242/dev.170522 PubMed DOI PMC

Nichols DH, Bouma JE, Kopecky BJ, et al. : Interaction with ectopic cochlear crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice. Cell Tissue Res. 2020; 380(3): 435–48. 10.1007/s00441-019-03163-y PubMed DOI PMC

Dastidar SG, Landrieu PMZ, D'Mello SR: FoxG1 promotes the survival of postmitotic neurons. J Neurosci. 2011; 31(2): 402–13. 10.1523/JNEUROSCI.2897-10.2011 PubMed DOI PMC

Domínguez-Frutos E, López-Hernández I, Vendrell V, et al. : N-myc controls proliferation, morphogenesis, and patterning of the inner ear. J Neurosci. 2011; 31(19): 7178–89. 10.1523/JNEUROSCI.0785-11.2011 PubMed DOI PMC

Kopecky B, Santi P, Johnson S, et al. : Conditional deletion of N-Myc disrupts neurosensory and non-sensory development of the ear. Dev Dyn. 2011; 240(6): 1373–90. 10.1002/dvdy.22620 PubMed DOI PMC

Rand TA, Sutou K, Tanabe K, et al. : MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition. Cell Rep. 2018; 23(2): 361–75. 10.1016/j.celrep.2018.03.057 PubMed DOI PMC

Pirvola U, Ylikoski J, Trokovic R, et al. : FGFR1 Is Required for the Development of the Auditory Sensory Epithelium. Neuron. 2002; 35(4): 671–80. 10.1016/s0896-6273(02)00824-3 PubMed DOI

Kersigo J, D'Angelo A, Gray BD, et al. : 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(4): 326–41. 10.1002/dvg.20714 PubMed DOI PMC