Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of cell fate in the sensory epithelia of the inner ear

Nature Reviews Neuroscience volume 7, pages 837–849 (2006)Cite this article

A Corrigendum to this article was published on 01 March 2007

Key Points

  • The first step in the development of inner ear sensory epithelia is the specification of prosensory patches. The factors that regulate the specification of the prosensory patches have not been fully determined, but signalling through Bmp4, jagged 1/Notch, Tbx1 and Sox2 clearly has an important role in this process.

  • Hair cells and supporting cells located in sensory epithelia in each of the auditory and vestibular regions develop with distinct cellular phenotypes. Until recently, with the exception of regional patterning genes that regulate the global patterning of the entire otocyst, the factors that determine whether a prosensory patch develops as auditory or vestibular were unknown.

  • A recent study showed that forced activation of the canonical WNT pathway in an auditory prosensory patch is sufficient to induce hair cells and supporting cells in that patch to develop as vestibular rather than auditory.

  • The regulation of cell cycle exit in the inner ear involves many of the same signalling molecules, such as RB1 and p27kip1, as other systems.

  • One intriguing aspect of the development of the mammalian cochlea, the counter gradients of terminal mitosis and cellular differentiation, seems to be uniquely regulated by expression of p27kip1.

  • The first cell type to be specified in each prosensory patch is the mechanosensory hair cell. Expression of the atonal homolog, Atoh1, is a key step in the specification of hair cells.

  • There is some debate about the role of ATOH1 as either a commitment factor or a differentiation factor, but there is clear data to demonstrate that ATOH1 is both necessary and sufficient for hair cell formation.

  • Developing hair cells generate at least two distinct signals that influence supporting cell development: an inhibitory signal, mediated through the Notch pathway, that prevents the cells from becoming hair cells and an inductive signal that recruits the cells to develop as supporting cells.

  • The demonstration that forced expression of Atoh1 is sufficient to induce development of hair cells and supporting cells even outside of prosensory patches has raised the possibility that the prosensory patch hypothesis should be reconsidered.

Abstract

The sensory epithelia of the inner ear contain mechanosensory hair cells and non-sensory supporting cells. Both classes of cell are heterogeneous, with phenotypes varying both between and within epithelia. The specification of individual cells as distinct types of hair cell or supporting cell is regulated through intra- and extracellular signalling pathways that have been poorly understood. However, new methodologies have resulted in significant steps forward in our understanding of the molecular pathways that direct cells towards these cell fates.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Anatomy of the auditory system, membranous labyrinth, and sensory epithelia.
Figure 2: The organ of Corti.
Figure 3: Development of the inner ear in the mouse.
Figure 4: Proposed roles for Notch signalling in the development of sensory epithelia.
Figure 5: Factors that direct sensory cell fates in the inner ear.

Similar content being viewed by others

References

  1. Eatock, R. A., Rusch, A., Lysakowski, A. & Saeki, M. Hair cells in mammalian utricles. Otolaryngol. Head Neck Surg. 119, 172–181 (1998).

    CAS  PubMed  Google Scholar 

  2. Hirokawa, N. The ultrastructure of the basilar papilla of the chick. J. Comp. Neurol. 181, 361–374 (1978).

    CAS  PubMed  Google Scholar 

  3. Nadol, J. B. Jr. Comparative anatomy of the cochlea and auditory nerve in mammals. Hear. Res. 34, 253–266 (1988).

    PubMed  Google Scholar 

  4. Lim, D. J. Functional structure of the organ of Corti: a review. Hear. Res. 22, 117–146 (1986).

    CAS  PubMed  Google Scholar 

  5. Manley, G. A. Some aspects of the evolution of hearing in vertebrates. Nature 230, 506–509 (1971).

    CAS  PubMed  Google Scholar 

  6. Barald, K. F. & Kelley, M. W. From placode to polarization: new tunes in inner ear development. Development 131, 4119–4130 (2004).

    CAS  PubMed  Google Scholar 

  7. Jacobson, A. G. The determination and positioning of the nose, lens and ear. III. Effects of reversing the antero–posterior axis of epidermis, neural plate and neural fold. J. Exp. Zool. 154, 293–303 (1963).

    CAS  PubMed  Google Scholar 

  8. Jacobson, A. G. Inductive processes in embryonic development. Science 152, 25–34 (1966).

    CAS  PubMed  Google Scholar 

  9. Martin, K. & Groves, A. K. Competence of cranial ectoderm to respond to Fgf signalling suggests a two-step model of otic placode induction. Development 133, 877–887 (2006).

    CAS  PubMed  Google Scholar 

  10. Riley, B. B. Genes controlling the development of the zebrafish inner ear and hair cells. Curr. Top. Dev. Biol. 57, 357–388 (2003).

    CAS  PubMed  Google Scholar 

  11. Riley, B. B. & Phillips, B. T. Ringing in the new ear: resolution of cell interactions in otic development. Dev. Biol. 261, 289–312 (2003).

    CAS  PubMed  Google Scholar 

  12. Nicolson, T. The genetics of hearing and balance in zebrafish. Annu. Rev. Genet. 39, 9–22 (2005).

    CAS  PubMed  Google Scholar 

  13. Groves, A. K. & Bronner-Fraser, M. Competence, specification and commitment in otic placode induction. Development 127, 3489–3499 (2000).

    CAS  PubMed  Google Scholar 

  14. Rubel, E. W. & Fritzsch, B. Auditory system development: primary auditory neurons and their targets. Annu. Rev. Neurosci. 25, 51–101 (2002).

    CAS  PubMed  Google Scholar 

  15. Carney, P. R. & Silver, J. Studies on cell migration and axon guidance in the developing distal auditory system of the mouse. J. Comp. Neurol. 215, 359–369 (1983).

    CAS  PubMed  Google Scholar 

  16. Adam, J. et al. Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with Drosophila sense-organ development. Development 125, 4645–4654 (1998).

    CAS  PubMed  Google Scholar 

  17. Zheng, W. et al. The role of Six1 in mammalian auditory system development. Development 130, 3989–4000 (2003).

    CAS  PubMed  Google Scholar 

  18. Riccomagno, M. M., Martinu, L., Mulheisen, M., Wu, D. K. & Epstein, D. J. Specification of the mammalian cochlea is dependent on Sonic hedgehog. Genes Dev. 16, 2365–2378 (2002). Gain- and loss-of-function mouse models were used to demonstrate that sonic hedgehog signalling originating at the ventral midline of the neural tube is required to specify the ventral region of the otocyst, including the cochlea.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Pujol, R. & Lavigne-Rebillard, M. Early stages of innervation and sensory cell differentiation in the human fetal organ of Corti. Acta Otolaryngol. Suppl. 423, 43–50 (1985).

    CAS  PubMed  Google Scholar 

  20. Sher, A. E. The embryonic and postnatal development of the inner ear of the mouse. Acta Otolaryngol. Suppl. 285, 1–77 (1971).

    CAS  PubMed  Google Scholar 

  21. Kikuchi, K. & Hilding, D. The development of the organ of Corti in the mouse. Acta Otolaryngol. 60, 207–222 (1965).

    CAS  PubMed  Google Scholar 

  22. Anniko, M., Nordemar, H. & Wersall, J. Genesis and maturation of vestibular hair cells. Adv. Otorhinolaryngol. 25, 7–11 (1979).

    CAS  PubMed  Google Scholar 

  23. Anniko, M. Cytodifferentiation of cochlear hair cells. Am. J. Otolaryngol. 4, 375–388 (1983).

    CAS  PubMed  Google Scholar 

  24. Ruben, R. J. Development of the inner ear of the mouse: a radioautographic study of terminal mitoses. Acta Otolaryngol. Suppl. 220, 1–44 (1967). A seminal study of the temporal and spatial patterns of terminal mitoses in the mouse inner ear. This work was also the first demonstration of the apical-to-basal gradient of terminal mitoses in the mammalian cochlea.

    Google Scholar 

  25. Sans, A. & Chat, M. Analysis of temporal and spatial patterns of rat vestibular hair cell differentiation by tritiated thymidine radioautography. J. Comp. Neurol. 206, 1–8 (1982).

    CAS  PubMed  Google Scholar 

  26. Li, H. et al. Islet-1 expression in the developing chicken inner ear. J. Comp. Neurol. 477, 1–10 (2004).

    CAS  PubMed  Google Scholar 

  27. Radde-Gallwitz, K. et al. Expression of Islet1 marks the sensory and neuronal lineages in the mammalian inner ear. J. Comp. Neurol. 477, 412–421 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chapman, S. C., Cai, Q., Bleyl, S. B. & Schoenwolf, G. C. Restricted expression of Fgf16 within the developing chick inner ear. Dev. Dyn. 235, 2276–2281 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Morsli, H., Choo, D., Ryan, A., Johnson, R. & Wu, D. K. Development of the mouse inner ear and origin of its sensory organs. J. Neurosci. 18, 3327–3335 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu, D. K. & Oh, S. H. Sensory organ generation in the chick inner ear. J. Neurosci. 16, 6454–6462 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Pujades, C., Kamaid, A., Alsina, B. & Giraldez, F. BMP-signaling regulates the generation of hair-cells. Dev. Biol. 292, 55–67 (2006).

    CAS  PubMed  Google Scholar 

  32. Bermingham-McDonogh, O. et al. Expression of Prox1 during mouse cochlear development. J. Comp. Neurol. 496, 172–186 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Oh, S. H., Johnson, R. & Wu, D. K. Differential expression of bone morphogenetic proteins in the developing vestibular and auditory sensory organs. J. Neurosci. 16, 6463–6475 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Cole, L. K. et al. Sensory organ generation in the chicken inner ear: contributions of bone morphogenetic protein 4, serrate1, and lunatic fringe. J. Comp. Neurol. 424, 509–520 (2000).

    CAS  PubMed  Google Scholar 

  35. Chang, W., Nunes, F. D., De Jesus-Escobar, J. M., Harland, R. & Wu, D. K. Ectopic noggin blocks sensory and nonsensory organ morphogenesis in the chicken inner ear. Dev. Biol. 216, 369–381 (1999).

    CAS  PubMed  Google Scholar 

  36. Gerlach, L. M. et al. Addition of the BMP4 antagonist, noggin, disrupts avian inner ear development. Development 127, 45–54 (2000).

    CAS  PubMed  Google Scholar 

  37. Li, H. et al. BMP4 signalling is involved in the generation of inner ear sensory epithelia. BMC Dev. Biol. 5, 16 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bruckner, K., Perez, L., Clausen, H. & Cohen, S. Glycosyltransferase activity of Fringe modulates Notch–Delta interactions. Nature 406, 411–415 (2000).

    CAS  PubMed  Google Scholar 

  39. Moloney, D. J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).

    CAS  PubMed  Google Scholar 

  40. Kiernan, A. E., Xu, J. & Gridley, T. The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet. 2, e4 (2006).

    PubMed  PubMed Central  Google Scholar 

  41. 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 129, 2495–2505 (2002).

    CAS  PubMed  Google Scholar 

  42. Lindsell, C. E., Boulter, J., diSibio, G., Gossler, A. & Weinmaster, G. Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development. Mol. Cell. Neurosci. 8, 14–27 (1996).

    CAS  PubMed  Google Scholar 

  43. Haddon, C., Jiang, Y. J., Smithers, L. & Lewis, J. Delta–Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: evidence from the mind bomb mutant. Development 125, 4637–4644 (1998).

    CAS  PubMed  Google Scholar 

  44. Panin, V. M., Papayannopoulos, V., Wilson, R. & Irvine, K. D. Fringe modulates Notch–ligand interactions. Nature 387, 908–12 (1997).

    CAS  PubMed  Google Scholar 

  45. Fleming, R. J., Gu, Y. & Hukriede, N. A. Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124, 2973–2981 (1997).

    CAS  PubMed  Google Scholar 

  46. de Celis, J. F., Tyler, D. M., de Celis, J. & Bray, S. J. Notch signalling mediates segmentation of the Drosophila leg. Development 125, 4617–4626 (1998).

    CAS  PubMed  Google Scholar 

  47. Klein, T. & Arias, A. M. Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development. Development 125, 2951–2962 (1998).

    CAS  PubMed  Google Scholar 

  48. Itoh, M. et al. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell 4, 67–82 (2003).

    CAS  PubMed  Google Scholar 

  49. Haddon, C. et al. Hair cells without supporting cells: further studies in the ear of the zebrafish mind bomb mutant. J. Neurocytol. 28, 837–850 (1999).

    CAS  PubMed  Google Scholar 

  50. Riley, B. B., Chiang, M., Farmer, L. & Heck, R. The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1. Development 126, 5669–5678 (1999).

    CAS  PubMed  Google Scholar 

  51. Kiernan, A. E., Cordes, R., Kopan, R., Gossler, A. & Gridley, T. The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development 132, 4353–4362 (2005).

    CAS  PubMed  Google Scholar 

  52. Katsube, K. & Sakamoto, K. Notch in vertebrates — molecular aspects of the signal. Int. J. Dev. Biol. 49, 369–374 (2005).

    CAS  PubMed  Google Scholar 

  53. Xue, Y. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum. Mol. Genet. 8, 723–730 (1999).

    CAS  PubMed  Google Scholar 

  54. Brooker, R., Hozumi, K. & Lewis, J. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133, 1277–1286 (2006).

    CAS  PubMed  Google Scholar 

  55. Tsai, H. et al. The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti. Hum. Mol. Genet. 10, 507–512 (2001).

    CAS  PubMed  Google Scholar 

  56. Kiernan, A. E. et al. The Notch ligand Jagged1 is required for inner ear sensory development. Proc. Natl. Acad. Sci. USA 98, 3873–3878 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Daudet, N. & Lewis, J. Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation. Development 132, 541–551 (2005).

    CAS  PubMed  Google Scholar 

  58. Kato, H. et al. Functional conservation of mouse Notch receptor family members. FEBS Lett. 395, 221–224 (1996).

    CAS  PubMed  Google Scholar 

  59. Merscher, S. et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629 (2001).

    CAS  PubMed  Google Scholar 

  60. Lindsay, E. A. et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).

    CAS  PubMed  Google Scholar 

  61. Jerome, L. A. & Papaioannou, V. E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).

    CAS  PubMed  Google Scholar 

  62. Raft, S., Nowotschin, S., Liao, J. & Morrow, B. E. Suppression of neural fate and control of inner ear morphogenesis by Tbx1. Development 131, 1801–1812 (2004). Used both mutant and knock-in models to demonstrate that Tbx1 is expressed in the prospective prosensory anlage and that it acts to inhibit cells with the otocyst from developing as SAG neuroblasts.

    CAS  PubMed  Google Scholar 

  63. Funke, B. et al. Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects. Hum. Mol. Genet. 10, 2549–2556 (2001).

    CAS  PubMed  Google Scholar 

  64. Vantrappen, G., Rommel, N., Cremers, C. W., Devriendt, K. & Frijns, J. P. The velo-cardio-facial syndrome: the otorhinolaryngeal manifestations and implications. Int. J. Pediatr. Otorhinolaryngol. 45, 133–141 (1998).

    CAS  PubMed  Google Scholar 

  65. Dong, S. et al. Circling, deafness, and yellow coat displayed by yellow submarine (ysb) and light coat and circling (lcc) mice with mutations on chromosome 3. Genomics 79, 777–784 (2002).

    CAS  PubMed  Google Scholar 

  66. Kiernan, A. E. et al. Sox2 is required for sensory organ development in the mammalian inner ear. Nature 434, 1031–1035 (2005). Two mice with ENU-induced mutations in an ear specific promoter for Sox2 are described. In each, reduced or complete loss of Sox2 expression leads to limited or completely lacking sensory epithelia. SOX2 is also shown to act upstream of ATOH1.

    CAS  PubMed  Google Scholar 

  67. Uchikawa, M., Kamachi, Y. & Kondoh, H. Two distinct subgroups of Group B Sox genes for transcriptional activators and repressors: their expression during embryonic organogenesis of the chicken. Mech. Dev. 84, 103–120 (1999).

    CAS  PubMed  Google Scholar 

  68. Bylund, M., Andersson, E., Novitch, B. G. & Muhr, J. Vertebrate neurogenesis is counteracted by Sox1–3 activity. Nature Neurosci. 6, 1162–1168 (2003).

    CAS  PubMed  Google Scholar 

  69. Graham, V., Khudyakov, J., Ellis, P. & Pevny, L. SOX2 functions to maintain neural progenitor identity. Neuron 39, 749–765 (2003).

    CAS  PubMed  Google Scholar 

  70. Stevens, C. B., Davies, A. L., Battista, S., Lewis, J. H. & Fekete, D. M. Forced activation of Wnt signalling alters morphogenesis and sensory organ identity in the chicken inner ear. Dev. Biol. 261, 149–164 (2003). Virally-mediated expression of an activated form of β-catenin or WNT3A in the chick otocyst is shown to induce patches of vestibular hair cells and supporting cells in the auditory sensory epithelium. This marks the first demonstration of a factor that can directly convert auditory sensory epithelia to a vestibular phenotype.

    CAS  PubMed  Google Scholar 

  71. Montcouquiol, M., Crenshaw, E. B. & Kelley, M. W. Noncanonical Wnt signaling and neural polarity. Annu. Rev. Neurosci. 29, 363–386 (2006).

    CAS  PubMed  Google Scholar 

  72. Dabdoub, A. & Kelley, M. W. Planar cell polarity and a potential role for a Wnt morphogen gradient in stereociliary bundle orientation in the mammalian inner ear. J. Neurobiol. 64, 446–457 (2005).

    CAS  PubMed  Google Scholar 

  73. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    CAS  PubMed  Google Scholar 

  74. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    CAS  PubMed  Google Scholar 

  75. Mantela, J. et al. The retinoblastoma gene pathway regulates the postmitotic state of hair cells of the mouse inner ear. Development 132, 2377–2388 (2005).

    CAS  PubMed  Google Scholar 

  76. Sage, C. et al. Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science 307, 1114–1118 (2005).

    CAS  PubMed  Google Scholar 

  77. Lee, Y. S., Liu, F. & Segil, N. A morphogenetic wave of p27Kip1 transcription directs cell cycle exit during organ of Corti development. Development 133, 2817–2826 (2006).

    CAS  PubMed  Google Scholar 

  78. Lowenheim, H. et al. Gene disruption of p27Kip1 allows cell proliferation in the postnatal and adult organ of corti. Proc. Natl Acad. Sci. USA 96, 4084–4088 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen, P. & Segil, N. p27Kip1 links cell proliferation to morphogenesis in the developing organ of Corti. Development 126, 1581–1590 (1999). This study, along with the study by Lowenheim et al . (reference 78) demonstrated that p27kip1 regulates cell cycle withdrawal in the developing organ of Corti.

    CAS  PubMed  Google Scholar 

  80. Fekete, D. M., Muthukumar, S. & Karagogeos, D. Hair cells and supporting cells share a common progenitor in the avian inner ear. J. Neurosci. 18, 7811–7821 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lang, H. & Fekete, D. M. Lineage analysis in the chicken inner ear shows differences in clonal dispersion for epithelial, neuronal, and mesenchymal cells. Dev. Biol. 234, 120–137 (2001).

    CAS  PubMed  Google Scholar 

  82. Kelley, M. W., Talreja, D. R. & Corwin, J. T. Replacement of hair cells after laser microbeam irradiation in cultured organs of corti from embryonic and neonatal mice. J. Neurosci. 15, 3013–3026 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Jones, J. E. & Corwin, J. T. Regeneration of sensory cells after laser ablation in the lateral line system: hair cell lineage and macrophage behavior revealed by time-lapse video microscopy. J. Neurosci. 16, 649–662 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Morest, D. K. & Cotanche, D. A. Regeneration of the inner ear as a model of neural plasticity. J. Neurosci. Res. 78, 455–460 (2004).

    CAS  PubMed  Google Scholar 

  85. Bermingham-McDonogh, O. & Rubel, E. W. Hair cell regeneration: winging our way towards a sound future. Curr. Opin. Neurobiol. 13, 119–126 (2003). A seminal study that demonstrated that ATOH1 is absolutely required for the formation of all hair cells in the inner ear. All markers of hair cells were lost in Atoh1 mutants.

    CAS  PubMed  Google Scholar 

  86. Bermingham, N. A. et al. Math1: an essential gene for the generation of inner ear hair cells. Science 284, 1837–1841 (1999).

    CAS  PubMed  Google Scholar 

  87. Lanford, P. J., Shailam, R., Norton, C. R., Gridley, T. & Kelley, M. W. Expression of Math1 and HES5 in the cochleae of wildtype and Jag2 mutant mice. J. Assoc. Res. Otolaryngol. 1, 161–171 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Jones, J. M., Montcouquiol, M., Dabdoub, A., Woods, C. & Kelley, M. W. Inhibitors of differentiation and DNA binding (Ids) regulate Math1 and hair cell formation during the development of the organ of Corti. J. Neurosci. 26, 550–558 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Zheng, J. L. & Gao, W. Q. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nature Neurosci. 3, 580–586 (2000). Electroporation of Atoh1 into non-sensory cells in postnatal cochlear explant cultures demonstrated that the expression of Atoh1 is sufficient to induce non-sensory cells to develop as hair cells.

    CAS  PubMed  Google Scholar 

  90. Woods, C., Montcouquiol, M. & Kelley, M. W. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nature Neurosci. 7, 1310–1318 (2004). Ectopic hair cells generated through over-expression of Atoh1 were shown to recruit surrounding non-sensory cells to develop as supporting cells, even in cochleae from Atoh1 mutants, demonstrating that Atoh1 is not directly required for supporting cell development.

    CAS  PubMed  Google Scholar 

  91. Kawamoto, K., Ishimoto, S., Minoda, R., Brough, D. E. & Raphael, Y. Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J. Neurosci. 23, 4395–4400 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Qian, D. et al. Basic helix-loop-helix gene Hes6 delineates the sensory hair cell lineage in the inner ear. Dev. Dyn. 235, 1689–1700 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Fritzsch, B. et al. Atoh1 null mice show directed afferent fiber growth to undifferentiated ear sensory epithelia followed by incomplete fiber retention. Dev. Dyn. 233, 570–583 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Lumpkin, E. A. et al. Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr. Patterns 3, 389–395 (2003).

    CAS  PubMed  Google Scholar 

  95. Norton, J. D. ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J. Cell Sci. 113, 3897–3905 (2000).

    CAS  PubMed  Google Scholar 

  96. Shailam, R. et al. Expression of proneural and neurogenic genes in the embryonic mammalian vestibular system. J. Neurocytol. 28, 809–819 (1999).

    CAS  PubMed  Google Scholar 

  97. Lanford, P. J. et al. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nature Genet. 21, 289–292 (1999). Deletion of Jag2 was shown to result in an increase in the number of cells that develop as hair cells in the mammalian cochlea. This study was the first demonstration of a functional role for Notch signalling in the ear.

    CAS  PubMed  Google Scholar 

  98. Morrison, A., Hodgetts, C., Gossler, A., Hrabe de Angelis, M. & Lewis, J. Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear. Mech. Dev. 84, 169–172 (1999).

    CAS  PubMed  Google Scholar 

  99. Zine, A. et al. Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. J. Neurosci. 21, 4712–4720 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Zheng, J. L., Shou, J., Guillemot, F., Kageyama, R. & Gao, W. Q. Hes1 is a negative regulator of inner ear hair cell differentiation. Development 127, 4551–4560 (2000).

    CAS  PubMed  Google Scholar 

  101. Murata, J., Tokunaga, A., Okano, H. & Kubo, T. Mapping of notch activation during cochlear development in mice: implications for determination of prosensory domain and cell fate diversification. J. Comp. Neurol. 497, 502–518 (2006).

    CAS  PubMed  Google Scholar 

  102. Pirvola, U. et al. The site of action of neuronal acidic fibroblast growth factor is the organ of Corti of the rat cochlea. Proc. Natl Acad. Sci. USA 92, 9269–9273 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Peters, K., Ornitz, D., Werner, S. & Williams, L. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev. Biol. 155, 423–430 (1993).

    CAS  PubMed  Google Scholar 

  104. Mueller, K. L., Jacques, B. E. & Kelley, M. W. Fibroblast growth factor signalling regulates pillar cell development in the organ of corti. J. Neurosci. 22, 9368–9377 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G. & Ornitz, D. M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet. 12, 390–397 (1996).

    CAS  PubMed  Google Scholar 

  106. Shim, K., Minowada, G., Coling, D. E. & Martin, G. R. Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signalling. Dev. Cell 8, 553–564 (2005).

    CAS  PubMed  Google Scholar 

  107. Pirvola, U. et al. FGFR1 is required for the development of the auditory sensory epithelium. Neuron 35, 671–680 (2002).

    CAS  PubMed  Google Scholar 

  108. Fritzsch, B. Development of inner ear afferent connections: forming primary neurons and connecting them to the developing sensory epithelia. Brain Res. Bull. 60, 423–433 (2003).

    PubMed  PubMed Central  Google Scholar 

  109. Fritzsch, B. & Beisel, K. W. Keeping sensory cells and evolving neurons to connect them to the brain: molecular conservation and novelties in vertebrate ear development. Brain Behav. Evol. 64, 182–197 (2004).

    CAS  PubMed  Google Scholar 

  110. Matei, V. et al. Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit. Dev. Dyn. 234, 633–650 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 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 11, R35–R44 (2000).

    CAS  PubMed  Google Scholar 

  112. Hassan, B. A. & Bellen, H. J. Doing the MATH: is the mouse a good model for fly development? Genes Dev. 14, 1852–1865 (2000).

    CAS  PubMed  Google Scholar 

  113. 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 20, 469–482 (1998).

    CAS  PubMed  Google Scholar 

  114. Satoh, T. & Fekete, D. M. Clonal analysis of the relationships between mechanosensory cells and the neurons that innervate them in the chicken ear. Development 132, 1687–1697 (2005).

    CAS  PubMed  Google Scholar 

  115. Zine, A. & de Ribaupierre, F. Notch/Notch ligands and Math1 expression patterns in the organ of Corti of wild-type and Hes1 and Hes5 mutant mice. Hear. Res. 170, 22–31 (2002).

    CAS  PubMed  Google Scholar 

  116. Itoh, M. & Chitnis, A. B. Expression of proneural and neurogenic genes in the zebrafish lateral line primordium correlates with selection of hair cell fate in neuromasts. Mech. Dev. 102, 263–266 (2001).

    CAS  PubMed  Google Scholar 

  117. Matsui, J. I., Parker, M. A., Ryals, B. M. & Cotanche, D. A. Regeneration and replacement in the vertebrate inner ear. Drug Discov. Today 10, 1307–1312 (2005).

    PubMed  Google Scholar 

  118. Ryan, A. F. The cell cycle and the development and regeneration of hair cells. Curr. Top Dev. Biol. 57, 449–466 (2003).

    PubMed  Google Scholar 

  119. Forge, A., Li, L. & Nevill, G. Hair cell recovery in the vestibular sensory epithelia of mature guinea pigs. J. Comp. Neurol. 397, 69–88 (1998).

    CAS  PubMed  Google Scholar 

  120. Adler, H. J. & Raphael, Y. New hair cells arise from supporting cell conversion in the acoustically damaged chick inner ear. Neurosci. Lett. 205, 17–20 (1996).

    CAS  PubMed  Google Scholar 

  121. Roberson, D. W., Alosi, J. A. & Cotanche, D. A. Direct transdifferentiation gives rise to the earliest new hair cells in regenerating avian auditory epithelium. J. Neurosci. Res. 78, 461–471 (2004).

    CAS  PubMed  Google Scholar 

  122. 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 441, 984–987 (2006).

    CAS  PubMed  Google Scholar 

  123. Izumikawa, M. et al. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Med. 11, 271–276 (2005).

    CAS  PubMed  Google Scholar 

  124. Martin, P. & Swanson, G. J. Descriptive and experimental analysis of the epithelial remodellings that control semicircular canal formation in the developing mouse inner ear. Dev. Biol. 159, 549–558 (1993).

    CAS  PubMed  Google Scholar 

  125. Kraman, M. & McCright, B. Functional conservation of Notch1 and Notch2 intracellular domains. FASEB J. 19, 1311–1313 (2005).

    CAS  PubMed  Google Scholar 

  126. Zhang, N., Martin, G. V., Kelley, M. W. & Gridley, T. A mutation in the Lunatic fringe gene suppresses the effects of a Jagged2 mutation on inner hair cell development in the cochlea. Curr. Biol. 10, 659–662 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author is supported by the Intramural Program of the National Institute on Deafness and Other Communication Disorders (National Institutes of Health). The author wishes to apologize to any of his colleagues whose work was necessarily excluded from this review because of word and length constraints. The author also wishes to thank D. Wu and N. Segil for providing valuable comments on an earlier version of this manuscript.

Author information

Authors and Affiliations

  1. Section on Developmental Neuroscience, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 35 Convent Dr., Bethesda, 20892, Maryland, USA

    Matthew W. Kelley

Authors
  1. Matthew W. Kelley
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Kelley's laboratory

Glossary

Mechanosensory hair cells

The primary transducers of pressure waves in the inner ear. Each is characterized by the presence of a stereociliary bundle on its lumenal surface.

Otocysts/otic vesicles

Bilateral ectodermal invaginations that constitute the primordia of the inner ear.

Organ of Corti

The sensory epithelium of the mammalian cochlea, characterized by the presence of inner and outer hair cells as well as at least four different types of supporting cell.

Otic placode

Bilateral thickening of the surface ectoderm located adjacent to the developing hindbrain. With continued development, placodes invaginate to form the otocyst.

Otic cup

Bilateral depressions of the otic placodes that form as a transitional phase between the otic placode and the otocyst.

Statoacoustic ganglion

(SAG). Also known as cranial nerve XIII. The cell bodies of the afferent nerves that innervate both the vestibular and auditory regions of the inner ear. All neurons in the ganglion are derived from cells that delaminate from the otocyst.

Cristae

The inner ear sensory epithelia associated with the three semi-circular canals.

Utricular/saccular maculae

Inner ear sensory epithelia associated with the utricle, a part of the vestibular system that mediates the perception of balance.

Anlage/anlagen

Describes a region in the otocyst that has become specified to develop as a prosensory patch but in which no morphological indications of prosensory identity have yet become obvious.

Deiters' cells

A specialized type of supporting cell within the organ of Corti that surrounds the outer hair cells.

T-box transcription factors

A family of transcription factors characterized by similarity in the DNA binding domain (the T domain).

DiGeorge syndrome

Also known as velocardiofacial syndrome. A genetic disorder caused by mutations in TBX1. Affected individuals can have malformations of the heart, face, limbs and auditory system.

Neuromast

A small patch of hair cell sensory epithelium located in the lateral line organs of fish and amphibians.

Basilar papilla

The auditory organ in birds. The basilar papilla is elongated like the mammalian cochlea but is straight rather than coiled.

Transdifferentiation

The direct conversion of a cell from one differentiated cell type to another. In the inner ear this refers to the direct conversion of supporting cells into hair cells.

Basic helix-loop-helix (bHLH) transcription factors

A family of transcription factors that are characterized by a conserved basic domain that mediates DNA binding and a conserved helix–loop–helix domain that mediates dimerization.

Inhibitors of differentiation and DNA binding

(IDs). A family of helix–loop–helix proteins. IDs are related to basic helix–loop–helix molecules but lack the basic domain required for DNA binding. As a result, their primary role is to compete with bHLHs for a common dimer partner.

Pillar cells

Specialized types of supporting cell found only in the organ of Corti in the mammalian cochlea. Inner and outer pillar cells combine to form the tunnel of Corti, a fluid-filled space between the inner and outer hair cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kelley, M. Regulation of cell fate in the sensory epithelia of the inner ear. Nat Rev Neurosci 7, 837–849 (2006). https://doi.org/10.1038/nrn1987

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1987

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing