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
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Eatock, R. A., Rusch, A., Lysakowski, A. & Saeki, M. Hair cells in mammalian utricles. Otolaryngol. Head Neck Surg. 119, 172–181 (1998).
Hirokawa, N. The ultrastructure of the basilar papilla of the chick. J. Comp. Neurol. 181, 361–374 (1978).
Nadol, J. B. Jr. Comparative anatomy of the cochlea and auditory nerve in mammals. Hear. Res. 34, 253–266 (1988).
Lim, D. J. Functional structure of the organ of Corti: a review. Hear. Res. 22, 117–146 (1986).
Manley, G. A. Some aspects of the evolution of hearing in vertebrates. Nature 230, 506–509 (1971).
Barald, K. F. & Kelley, M. W. From placode to polarization: new tunes in inner ear development. Development 131, 4119–4130 (2004).
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).
Jacobson, A. G. Inductive processes in embryonic development. Science 152, 25–34 (1966).
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).
Riley, B. B. Genes controlling the development of the zebrafish inner ear and hair cells. Curr. Top. Dev. Biol. 57, 357–388 (2003).
Riley, B. B. & Phillips, B. T. Ringing in the new ear: resolution of cell interactions in otic development. Dev. Biol. 261, 289–312 (2003).
Nicolson, T. The genetics of hearing and balance in zebrafish. Annu. Rev. Genet. 39, 9–22 (2005).
Groves, A. K. & Bronner-Fraser, M. Competence, specification and commitment in otic placode induction. Development 127, 3489–3499 (2000).
Rubel, E. W. & Fritzsch, B. Auditory system development: primary auditory neurons and their targets. Annu. Rev. Neurosci. 25, 51–101 (2002).
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).
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).
Zheng, W. et al. The role of Six1 in mammalian auditory system development. Development 130, 3989–4000 (2003).
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.
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).
Sher, A. E. The embryonic and postnatal development of the inner ear of the mouse. Acta Otolaryngol. Suppl. 285, 1–77 (1971).
Kikuchi, K. & Hilding, D. The development of the organ of Corti in the mouse. Acta Otolaryngol. 60, 207–222 (1965).
Anniko, M., Nordemar, H. & Wersall, J. Genesis and maturation of vestibular hair cells. Adv. Otorhinolaryngol. 25, 7–11 (1979).
Anniko, M. Cytodifferentiation of cochlear hair cells. Am. J. Otolaryngol. 4, 375–388 (1983).
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.
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).
Li, H. et al. Islet-1 expression in the developing chicken inner ear. J. Comp. Neurol. 477, 1–10 (2004).
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).
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).
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).
Wu, D. K. & Oh, S. H. Sensory organ generation in the chick inner ear. J. Neurosci. 16, 6454–6462 (1996).
Pujades, C., Kamaid, A., Alsina, B. & Giraldez, F. BMP-signaling regulates the generation of hair-cells. Dev. Biol. 292, 55–67 (2006).
Bermingham-McDonogh, O. et al. Expression of Prox1 during mouse cochlear development. J. Comp. Neurol. 496, 172–186 (2006).
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).
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).
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).
Gerlach, L. M. et al. Addition of the BMP4 antagonist, noggin, disrupts avian inner ear development. Development 127, 45–54 (2000).
Li, H. et al. BMP4 signalling is involved in the generation of inner ear sensory epithelia. BMC Dev. Biol. 5, 16 (2005).
Bruckner, K., Perez, L., Clausen, H. & Cohen, S. Glycosyltransferase activity of Fringe modulates Notch–Delta interactions. Nature 406, 411–415 (2000).
Moloney, D. J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).
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).
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).
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).
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).
Panin, V. M., Papayannopoulos, V., Wilson, R. & Irvine, K. D. Fringe modulates Notch–ligand interactions. Nature 387, 908–12 (1997).
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).
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).
Klein, T. & Arias, A. M. Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development. Development 125, 2951–2962 (1998).
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).
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).
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).
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).
Katsube, K. & Sakamoto, K. Notch in vertebrates — molecular aspects of the signal. Int. J. Dev. Biol. 49, 369–374 (2005).
Xue, Y. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum. Mol. Genet. 8, 723–730 (1999).
Brooker, R., Hozumi, K. & Lewis, J. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133, 1277–1286 (2006).
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).
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).
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).
Kato, H. et al. Functional conservation of mouse Notch receptor family members. FEBS Lett. 395, 221–224 (1996).
Merscher, S. et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629 (2001).
Lindsay, E. A. et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).
Jerome, L. A. & Papaioannou, V. E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).
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.
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).
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).
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).
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.
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).
Bylund, M., Andersson, E., Novitch, B. G. & Muhr, J. Vertebrate neurogenesis is counteracted by Sox1–3 activity. Nature Neurosci. 6, 1162–1168 (2003).
Graham, V., Khudyakov, J., Ellis, P. & Pevny, L. SOX2 functions to maintain neural progenitor identity. Neuron 39, 749–765 (2003).
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.
Montcouquiol, M., Crenshaw, E. B. & Kelley, M. W. Noncanonical Wnt signaling and neural polarity. Annu. Rev. Neurosci. 29, 363–386 (2006).
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).
Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).
Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).
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).
Sage, C. et al. Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science 307, 1114–1118 (2005).
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).
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).
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.
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).
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).
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).
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).
Morest, D. K. & Cotanche, D. A. Regeneration of the inner ear as a model of neural plasticity. J. Neurosci. Res. 78, 455–460 (2004).
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.
Bermingham, N. A. et al. Math1: an essential gene for the generation of inner ear hair cells. Science 284, 1837–1841 (1999).
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).
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).
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.
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.
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).
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).
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).
Lumpkin, E. A. et al. Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr. Patterns 3, 389–395 (2003).
Norton, J. D. ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J. Cell Sci. 113, 3897–3905 (2000).
Shailam, R. et al. Expression of proneural and neurogenic genes in the embryonic mammalian vestibular system. J. Neurocytol. 28, 809–819 (1999).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
Pirvola, U. et al. FGFR1 is required for the development of the auditory sensory epithelium. Neuron 35, 671–680 (2002).
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).
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).
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).
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).
Hassan, B. A. & Bellen, H. J. Doing the MATH: is the mouse a good model for fly development? Genes Dev. 14, 1852–1865 (2000).
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).
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).
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).
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).
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).
Ryan, A. F. The cell cycle and the development and regeneration of hair cells. Curr. Top Dev. Biol. 57, 449–466 (2003).
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).
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).
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).
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).
Izumikawa, M. et al. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Med. 11, 271–276 (2005).
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).
Kraman, M. & McCright, B. Functional conservation of Notch1 and Notch2 intracellular domains. FASEB J. 19, 1311–1313 (2005).
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).
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
Ethics declarations
Competing interests
The author declares no competing financial interests.
Related links
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
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
Issue Date:
DOI: https://doi.org/10.1038/nrn1987
This article is cited by
-
Loss of Pax3 causes reduction of melanocytes in the developing mouse cochlea
Scientific Reports (2024)
-
Dispensable role of Rac1 and Rac3 after cochlear hair cell specification
Journal of Molecular Medicine (2023)
-
AAV-Net1 facilitates the trans-differentiation of supporting cells into hair cells in the murine cochlea
Cellular and Molecular Life Sciences (2023)
-
Early development of the cochlea of the common marmoset, a non-human primate model
Neural Development (2022)
-
Temporal and regulatory dynamics of the inner ear transcriptome during development in mice
Scientific Reports (2022)