Journal of Zhejiang University-SCIENCE B

, Volume 20, Issue 2, pp 146–155 | Cite as

Atoh1 regulation in the cochlea: more than just transcription

  • Yen-Fu ChengEmail author


More than 80% of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons, and a lack of regeneration of these cells leads to permanent hearing loss. Therefore, the regeneration of lost hair cells is an important goal for the treatment of deafness. Atoh1 is a basic helix-loop-helix (bHLH) transcription factor that is critical in both the development and regeneration of cochlear hair cells. Atoh1 is transcriptionally regulated by several signaling pathways, including Notch and Wnt signalings. At the post-translational level, it is regulated through the ubiquitin-proteasome pathway. In vitro and in vivo studies have revealed that manipulation of these signaling pathways not only controls development, but also leads to the regeneration of cochlear hair cells after damage. Recent progress toward understanding the signaling networks involved in hair cell development and regeneration has led to the development of new strategies to replace lost hair cells. This review focuses on our current understanding of the signaling pathways that regulate Atoh1 in the cochlea.

Key words

Atoh1 Huwe1 Cochlea Hair cells Regeneration Post-translational regulation 

Atoh1 转录因子在耳蜗内的转译后调节

摘 要

Atoh1 属于bHLH 转录因子家族成员, 其对耳蜗毛细胞的胚胎发育及损伤后再生具有重要作用。 许多讯号通道在转录水平上对 Atoh1 有调节作用, 包括 Notch 和 Wnt 通道。 在蛋白转译后水平, Atoh1 是经由泛素-蛋白酶通道所调节。 体外细胞实验及体内动物实验都显示: 经由上述讯号通道的调节手段不仅影响耳蜗发育, 也导致毛细胞的损伤后再生。 本综述回顾了耳蜗内各个对 Atoh1 调节讯号通道研究的进展, 并聚焦于泛素-蛋白酶通道对 Atoh1 进行转译后调节及其对毛细胞发 育的影响。


Atoh1 Huwe1 耳蜗 毛细胞 再生 转译后调节 

CLC number



  1. Akil, O., Seal, R.P., Burke, K., et al., 2012. Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron, 75(2): 283–293. Scholar
  2. Askew, C., Rochat, C., Pan, B., et al., 2015. Tmc gene therapy restores auditory function in deaf mice. Sci. Transl. Med., 7(295): 295ra108. Scholar
  3. Atkinson, P.J., Wise, A.K., Flynn, B.O., et al., 2014. Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs. PLoS ONE, 9(7): e102077. Scholar
  4. Ayrault, O., Zhao, H., Zindy, F., et al., 2010. Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells. Cancer Res., 70(13): 5618–5627. Scholar
  5. Ben-Arie, N., McCall, A.E., Berkman, S., et al., 1996. Evolutionary conservation of sequence and expression of the bHLH protein atonal suggests a conserved role in neurogenesis. Hum. Mol. Genet., 5(9): 1207–1216. Scholar
  6. Ben-Arie, N., Bellen, H.J., Armstrong, D.L., et al., 1997. Math1 is essential for genesis of cerebellar granule neurons. Nature, 390(6656): 169–172. Scholar
  7. Ben-Arie, N., Hassan, B.A., Bermingham, N.A., et al., 2000. Functional conservation of atonal and Math1 in the CNS and PNS. Development, 127(5): 1039–1048.Google Scholar
  8. Bermingham, N.A., Hassan, B.A., Price, S.D., et al., 1999. Math1: an essential gene for the generation of inner ear hair cells. Science, 284(5421): 1837–1841. Scholar
  9. Bertrand, N., Castro, D.S., Guillemot, F., 2002. Proneural genes and the specification of neural cell types. Nat. Rev. Neurosci., 3(7): 517–530. Scholar
  10. Bossuyt, W., Kazanjian, A., de Geest, N., et al., 2009. Atonal homolog 1 is a tumor suppressor gene. PLoS Biol., 7(2): e1000039. Scholar
  11. Bramhall, N.F., Shi, F., Arnold, K., et al., 2014. Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea. Stem Cell Rep., 2(3): 311–322. Scholar
  12. Brooker, R., Hozumi, K., Lewis, J., 2006. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development, 133(7): 1277–1286. Scholar
  13. Cai, T., Seymour, M.L., Zhang, H., et al., 2013. Conditional deletion of Atoh1 reveals distinct critical periods for survival and function of hair cells in the organ of Corti. J. Neurosci., 33(24): 10110–10122. Scholar
  14. Chen, D., Kon, N., Li, M., et al., 2005. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell, 121(7): 1071–1083. Scholar
  15. Chen, P., Johnson, J.E., Zoghbi, H.Y., et al., 2002. The role of Math1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination. Development, 129(10): 2495–2505.Google Scholar
  16. Cheng, Y.F., Tong, M., Edge, A.S.B., 2016. Destabilization of Atoh1 by E3 ubiquitin ligase Huwe1 and casein kinase 1 is essential for normal sensory hair cell development. J. Biol. Chem., 291(40): 21096–21109. Scholar
  17. Cox, B.C., Chai, R., Lenoir, A., et al., 2014. Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development, 141(4): 816–829. Scholar
  18. D’Arca, D., Zhao, X., Xu, W., et al., 2010. Huwe1 ubiquitin ligase is essential to synchronize neuronal and glial differentiation in the developing cerebellum. Proc. Natl. Acad. Sci. USA, 107(13): 5875–5880. Scholar
  19. Davis, A.C., 1983. Hearing disorders in the population: first phase findings of the MRC national study of hearing. In: Lutman, M.E., Haggard, M.P. (Eds.), Hearing Science and Hearing Disorders. Academic Press Inc. (London) Ltd., London, p.35–60. Scholar
  20. Dominguez-Brauer, C., Hao, Z., Elia, A.J., et al., 2016. Mule regulates the intestinal stem cell niche via the Wnt pathway and targets EphB3 for proteasomal and lysosomal degradation. Cell Stem Cell, 19(2): 205–216. Scholar
  21. Flora, A., Garcia, J., Thaller, C., et al., 2007. The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc. Natl. Acad. Sci. USA, 104(39): 15382–15387. Scholar
  22. Flora, A., Klisch, T.J., Schuster, G., et al., 2009. Deletion of Atoh1 disrupts sonic hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science, 326(5958): 1424–1427. Scholar
  23. Forge, A., Li, L., Corwin, J.T., et al., 1993. Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science, 259(5101): 1616–1619. Scholar
  24. Forget, A., Bihannic, L., Cigna, S.M., et al., 2014. SHH signaling protects Atoh1 from degradation mediated by the E3 ubiquitin ligase Huwe1 in neural precursors. Dev. Cell, 29(6): 649–661. Scholar
  25. Fritzsch, B., 2003. Development of inner ear afferent connections: forming primary neurons and connecting them to the developing sensory epithelia. Brain Res. Bull., 60(5–6): 423–433. Scholar
  26. Fröhlich, A., Kisielow, J., Schmitz, I., et al., 2009. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science, 324(5934): 1576–1580. Scholar
  27. Gregorieff, A., Clevers, H., 2005. Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev., 19(8): 877–890. Scholar
  28. Gubbels, S.P., Woessner, D.W., Mitchell, J.C., et al., 2008. Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature, 455(7212): 537–541. Scholar
  29. Hall, J.R., Kow, E., Nevis, K.R., et al., 2007. Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Mol. Biol. Cell, 18(9): 3340–3350. Scholar
  30. Helms, A.W., Gowan, K., Abney, A., et al., 2001. Overexpression of MATH1 disrupts the coordination of neural differentiation in cerebellum development. Mol. Cell. Neurosci., 17(4): 671–682. Scholar
  31. Hu, Z., Ulfendahl, M., 2006. Cell replacement therapy in the inner ear. Stem Cells Dev., 15(3): 449–459. Scholar
  32. Hu, Z., Andäng, M., Ni, D., et al., 2005. Neural cograft stimulates the survival and differentiation of embryonic stem cells in the adult mammalian auditory system. Brain Res., 1051(1): 137–144. Scholar
  33. Huang, W.H., Tupal, S., Huang, T.W., et al., 2012. Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood. Neuron, 75(5): 799–809. Scholar
  34. Husseman, J., Raphael, Y., 2009. Gene therapy in the inner ear using adenovirus vectors. In: Ryan, A.F. (Ed.), Gene Therapy of Cochlear Deafness. Advances in Oto-Rhino-Laryngology. Karger, Basel, Vol. 66, p.37–51. Scholar
  35. Incesulu, A., Nadol, J.B., 1998. Correlation of acoustic threshold measures and spiral ganglion cell survival in severe to profound sensorineural hearing loss: implications for cochlear implantation. Ann. Otol. Rhinol. Laryngol., 107(11): 906–911. Scholar
  36. Izumikawa, M., Minoda, R., Kawamoto, K., et al., 2005. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat. Med., 11(3): 271–276. Scholar
  37. Jahan, I., Pan, N., Kersigo, J., et al., 2013. Beyond generalized hair cells: molecular cues for hair cell types. Hear. Res., 297:30–41. Scholar
  38. Jansson, L., Kim, G.S., Cheng, A.G., 2015. Making sense of Wnt signaling-linking hair cell regeneration to development. Front. Cell. Neurosci., 9:66. Scholar
  39. Jarriault, S., Brou, C., Logeat, F., et al., 1995. Signalling downstream of activated mammalian Notch. Nature, 377(6547): 355–358. Scholar
  40. Jeon, S.J., Fujioka, M., Kim, S.C., et al., 2011. Notch signaling alters sensory or neuronal cell fate specification of inner ear stem cells. J. Neurosci., 31(23): 8351–8358. Scholar
  41. Kelley, M.W., 2003. Cell adhesion molecules during inner ear and hair cell development, including notch and its ligands. Curr. Top. Dev. Biol., 57:321–356. Scholar
  42. Kelley, M.W., 2006. Regulation of cell fate in the sensory epithelia of the inner ear. Nat. Rev. Neurosci., 7(11): 837–849. Scholar
  43. Kurokawa, M., Kim, J., Geradts, J., et al., 2013. A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. Sci. Signal., 6(274):ra32. Scholar
  44. Lanford, P.J., Lan, Y., Jiang, R., et al., 1999. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat. Genet., 21(3): 289–292. Scholar
  45. Li, W., Wu, J., Yang, J., et al., 2015. Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc. Natl. Acad. Sci. USA, 112(1): 166–171. Scholar
  46. Liu, Z., Dearman, J.A., Cox, B.C., et al., 2012. Age-dependent in vivo conversion of mouse cochlear pillar and Deiters’ cells to immature hair cells by Atoh1 ectopic expression. J. Neurosci., 32(19): 6600–6610. Scholar
  47. Liu, Z., Fang, J., Dearman, J., et al., 2014. In vivo generation of immature inner hair cells in neonatal mouse cochleae by ectopic Atoh1 expression. PLoS ONE, 9(2): e89377. Scholar
  48. Lo, L.C., Johnson, J.E., Wuenschell, C.W., et al., 1991. Mammalian achaete-scute homolog 1 is transiently expressed by spatially restricted subsets of early neuroepithelial and neural crest cells. Genes Dev., 5(9): 1524–1537. Scholar
  49. Maass, J.C., Gu, R., Basch, M.L., et al., 2015. Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea. Front. Cell. Neurosci., 9:110. Scholar
  50. Maksimovic, S., Nakatani, M., Baba, Y., et al., 2014. Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature, 509(7502): 617–621. Scholar
  51. McLean, W.J., Yin, X., Lu, L., et al., 2017. Clonal expansion of Lgr5-positive cells from mammalian cochlea and highpurity generation of sensory hair cells. Cell Rep., 18(8): 1917–1929. Scholar
  52. Mianné, J., Chessum, L., Kumar, S., et al., 2016. Correction of the auditory phenotype in C57BL/6N mice via CRISPR/ Cas9-mediated homology directed repair. Genome Med., 8(1): 16. Scholar
  53. Miesegaes, G.R., Klisch, T.J., Thaller, C., et al., 2009. Identification and subclassification of new Atoh1 derived cell populations during mouse spinal cord development. Dev. Biol., 327(2): 339–351. Scholar
  54. Mizutari, K., Fujioka, M., Hosoya, M., et al., 2013. Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron, 77(1): 58–69. Scholar
  55. Morrison, K.M., Miesegaes, G.R., Lumpkin, E.A., et al., 2009. Mammalian Merkel cells are descended from the epidermal lineage. Dev. Biol., 336(1): 76–83. Scholar
  56. Naujokat, C., Šaric, T., 2007. Concise review: role and function of the ubiquitin-proteasome system in mammalian stem and progenitor cells. Stem Cells, 25(10): 2408–2418. Scholar
  57. Ni, W., Lin, C., Guo, L., et al., 2016. Extensive supporting cell proliferation and mitotic hair cell generation by in vivo genetic reprogramming in the neonatal mouse cochlea. J. Neurosci., 36(33): 8734–8745. Scholar
  58. Ohyama, T., Mohamed, O.A., Taketo, M.M., et al., 2006. Wnt signals mediate a fate decision between otic placode and epidermis. Development, 133(5): 865–875. Scholar
  59. Pan, B., Askew, C., Galvin, A., et al., 2017. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat. Biotechnol., 35(3): 264–272. Scholar
  60. Pan, N., Jahan, I., Kersigo, J., et al., 2012. A novel Atoh1 “self-terminating” mouse model reveals the necessity of proper Atoh1 level and duration for hair cell differentiation and viability. PLoS ONE, 7(1): e30358. Scholar
  61. Riccomagno, M., Takada, S., Epstein, D., 2005. Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes Dev., 19(13): 1612–1623. Scholar
  62. Richardson, R.T., Atkinson, P.J., 2015. Atoh1 gene therapy in the cochlea for hair cell regeneration. Expert Opin. Biol. Ther., 15(3): 417–430. Scholar
  63. Rose, M.F., Ahmad, K.A., Thaller, C., et al., 2009. Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for math1. Proc. Natl. Acad. Sci. USA, 106(52): 22462–22467. Scholar
  64. Ross, S.E., Greenberg, M.E., Stiles, C.D., 2003. Basic helixloop-helix factors in cortical development. Neuron, 39(1): 13–25. Scholar
  65. Ruffault, P.L., D’Autréaux, F., Hayes, J.A., et al., 2015. The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO2. eLife, 4:e07051. Scholar
  66. Shi, F., Cheng, Y.F., Wang, X.L., et al., 2010. ß-Catenin up-regulates Atoh1 expression in neural progenitor cells by interaction with an Atoh1 3′ enhancer. J. Biol. Chem., 285(1): 392–400. Scholar
  67. Shi, F., Kempfle, J.S., Edge, A.S.B., 2012. Wnt-responsive Lgr5-expressing stem cells are hair cell progenitors in the cochlea. J. Neurosci., 32(28): 9639–9648. Scholar
  68. Shi, F., Hu, L., Edge, A.S.B., 2013. Generation of hair cells in neonatal mice by ß-catenin overexpression in Lgr5-positive cochlear progenitors. Proc. Natl. Acad. Sci. USA, 110(34): 13851–13856. Scholar
  69. Shi, F., Hu, L., Jacques, B.E., et al., 2014. ß-Catenin is required for hair-cell differentiation in the cochlea. J. Neurosci., 34(19): 6470–6479. Scholar
  70. Shroyer, N.F., Helmrath, M.A., Wang, V.Y.C., et al., 2007. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology, 132(7): 2478–2488. Scholar
  71. Shu, Y., Tao, Y., Wang, Z., et al., 2016. Identification of adeno-associated viral vectors that target neonatal and adult mammalian inner ear cell subtypes. Hum. Gene Ther., 27(9): 687–699. Scholar
  72. Staecker, H., Praetorius, M., Baker, K., et al., 2007. Vestibular hair cell regeneration and restoration of balance function induced by Math1 gene transfer. Otol. Neurotol., 28(2): 223–231. Scholar
  73. Stevens, C.B., Davies, A.L., Battista, S., et al., 2003. Forced activation of Wnt signaling alters morphogenesis and sensory organ identity in the chicken inner ear. Dev. Biol., 261(1): 149–164. Scholar
  74. Tai, H.C., Schuman, E.M., 2008. Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat. Rev. Neurosci., 9(11): 826–838. Scholar
  75. Takebayashi, S., Yamamoto, N., Yabe, D., et al., 2007. Multiple roles of Notch signaling in cochlear development. Dev. Biol., 307(1): 165–178. Scholar
  76. Tiveron, M.C., Pattyn, A., Hirsch, M.R., et al., 2003. Role of Phox2b and Mash1 in the generation of the vestibular efferent nucleus. Dev. Biol., 260(1): 46–57. Scholar
  77. Tsuchiya, K., Nakamura, T., Okamoto, R., et al., 2007. Reciprocal targeting of Hath1 and ß-catenin by Wnt glycogen synthase kinase 3ß in human colon cancer. Gastroenterology, 132(1): 208–220. Scholar
  78. Urbán, N., van den Berg, D.L.C., Forget, A., et al., 2016. Return to quiescence of mouse neural stem cells by degradation of a proactivation protein. Science, 353(6296): 292–295. Scholar
  79. VanDussen, K.L., Samuelson, L.C., 2010. Mouse atonal homolog 1 directs intestinal progenitors to secretory cell rather than absorptive cell fate. Dev. Biol., 346(2): 215–223. Scholar
  80. van Keymeulen, A., Mascre, G., Youseff, K.K., et al., 2009. Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J. Cell Biol., 187(1): 91–100. Scholar
  81. Varshavsky, A., 1991. Naming a targeting signal. Cell, 64(1): 13–15. Scholar
  82. Wang, T., Chai, R., Kim, G.S., et al., 2015. Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nat. Commun., 6:6613. Scholar
  83. Wang, V.Y., Rose, M.F., Zoghbi, H.Y., 2005. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron, 48(1): 31–43. Scholar
  84. Warchol, M.E., Lambert, P.R., Goldstein, B.J., et al., 1993. Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science, 259(5101): 1619–1623. Scholar
  85. WHO (World Health Organization), 2017. Deafness and hearing loss. Fact sheet, WHO Media Centre.Google Scholar
  86. Woods, C., Montcouquiol, M., Kelley, M.W., 2004. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat. Neurosci., 7(12): 1310–1318. Scholar
  87. Wright, M.C., Reed-Geaghan, E.G., Bolock, A.M., et al., 2015. Unipotent, Atoh1+ progenitors maintain the Merkel cell population in embryonic and adult mice. J. Cell Biol., 208(3): 367–379. Scholar
  88. Yamamoto, N., Tanigaki, K., Tsuji, M., et al., 2006. Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas. J. Mol. Med., 84(1): 37–45. Scholar
  89. Yang, H., Xie, X., Deng, M., et al., 2010. Generation and characterization of Atoh1-Cre knock-in mouse line. Genesis, 48(6): 407–413. Scholar
  90. Yang, Q., Bermingham, N.A., Finegold, M.J., et al., 2001. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science, 294(5549): 2155–2158. Scholar
  91. Zhao, H., Ayrault, O., Zindy, F., et al., 2008. Posttranscriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes Dev., 22(6): 722–727. Scholar
  92. Zhao, X., Heng, J.I.T., Guardavaccaro, D., et al., 2008. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat. Cell Biol., 10(6): 643–653. Scholar
  93. Zhao, X., D’Arca, D., Lim, W.K., et al., 2009. The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev. Cell, 17(2): 210–221. Scholar
  94. Zheng, J.L., Gao, W.Q., 2000. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat. Neurosci., 3(6): 580–586. Scholar
  95. Zou, B., Mittal, R., Grati, M., et al., 2015. The application of genome editing in studying hearing loss. Hear. Res., 327:102–108. Scholar
  96. Zuris, J.A., Thompson, D.B., Shu, Y., et al., 2015. Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat. Biotechnol., 33(1): 73–80. Scholar

Copyright information

© Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Otology and LaryngologyHarvard Medical SchoolBostonUSA
  2. 2.Eaton-Peabody LaboratoryMassachusetts Eye and Ear InfirmaryBostonUSA
  3. 3.Department of Medical ResearchTaipei Veterans General HospitalTaipeiChina
  4. 4.Department of Otolaryngology-Head and Neck SurgeryTaipei Veterans General HospitalTaipeiChina
  5. 5.School of MedicineYang-Ming UniversityTaipeiChina
  6. 6.Department of Speech Language Pathology and AudiologyTaipei University of Nursing and Health ScienceTaipeiChina

Personalised recommendations