, Volume 9, Issue 3, pp 255–264 | Cite as

Programmed cell death in the development of the vertebrate inner ear

  • Y. LeónEmail author
  • S. Sánchez-Galiano
  • I. Gorospe


Programmed cell death is known to be an essential process for accurate ontogeny during the normal development of the inner ear. The inner ear is a complex sensory organ responsible for equilibrium and sound detection in vertebrates. In all vertebrates, the inner ear develops from a single ectodermic patch on the surface of the embryo’s head, which undergoes a series of morphological changes to give rise to the complex structure of the adult inner ear. Enlargement and morphogenesis of the inner ear primordium is likely to depend on cellular division, growth, migration, differentiation and apoptosis. Here we describe the regions of programmed cell death that contribute to the final morphological aspect of the adult inner ear. The few studies that focus on the molecules that control this process during inner ear development indicate that the molecules and intracellular signaling pathways activated during the apoptotic response in the inner ear are similar to the previously described for the nervous system. In this review, we will describe some of the growth factors and key pathways that regulate pro- and anti-apoptotic signals and how they cross talk to determine the apoptotic or survival fate of cells in the development of the inner ear.

apoptosis inner ear insulin-like growth factor-I (IGF-I) morphogenesis nerve growth factor (NGF) 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770–776.CrossRefPubMedGoogle Scholar
  2. 2.
    Glücksmann A. Cell deaths in normal vertebrate ontogeny. Biological Rev 1951; 26: 59–86.Google Scholar
  3. 3.
    Raff MC. Social controls on cell survival and cell death. Nature 1992; 356: 397–400.CrossRefPubMedGoogle Scholar
  4. 4.
    Vaux DL, Korsmeyer SJ. Cell death in development. Cell 1999; 22: 245–254.Google Scholar
  5. 5.
    Hamburger V, Oppenheim RW. Naturally occurring neuronal death in vertebrates. Neurosci Comment 1982; 1: 39–55.Google Scholar
  6. 6.
    Sanders EJ, Wride MA. Programmed cell death in development. Int Rev Cytol 1995; 163: 105–173.PubMedGoogle Scholar
  7. 7.
    Saunders JW. Death in embryonic systems. Science 1966; 154: 604–610.PubMedGoogle Scholar
  8. 8.
    Nishikori T, Hatta T, Kawauchi H, Otani H. Apoptosis during inner ear development in human and mouse embryos: An analysis by computer-assisted three-dimensional reconstruction. Anat Embryol 1999; 200: 19–26.PubMedGoogle Scholar
  9. 9.
    Fritzsch B, Barald KF, Lomax MI. Early embryology of the vertebrate ear. In: Rubel EW, Popper AN, Fay RR, eds. Development of the Auditory System. New York: Springer-Verlag 1998: 80–145.Google Scholar
  10. 10.
    Bissonnete JP, Fekete DM. Standard atlas of the gross anatomy of the developing inner ear of the chicken. J Comp Neurol 1996; 368: 620–630.PubMedGoogle Scholar
  11. 11.
    Bever MM, Fekete DM. Atlas of the developing inner ear in zebrafish. Dev Dyn 2002; 223: 536–543.PubMedGoogle Scholar
  12. 12.
    Bever MM, Jean YY, Fekete DM. Three-dimensional morphology of inner ear development in Xenopus Laevis. Dev Dyn 2003; 227: 422–430.PubMedGoogle Scholar
  13. 13.
    Morsli H, Choo D, Ryan A, Johnson R, Wu DK. Development of the mouse inner ear and origin of its sensory organs. J Neurosci 1998; 18: 3327–3335.PubMedGoogle Scholar
  14. 14.
    Riley BB, Phillips BT. Ringing in the new ear: Resolution of cell interactions in otic development. Dev Biol 2003; 261: 289–312.PubMedGoogle Scholar
  15. 15.
    Martelli AM, Zweyer M, Ochs RL, Tazzari PL, Tabellini G, Narducci P, Bortul R. Nuclear apoptotic changes: An overview. J Cell Biochem 2001; 82: 634–646.PubMedGoogle Scholar
  16. 16.
    Torres M, Giraldez F. The development of the vertebrate inner ear. Mech Dev 1998; 71: 5–21.PubMedGoogle Scholar
  17. 17.
    Alvarez IS, NavascÚes J. Shaping, invagination and closure of the chick embryo otic vesicle: Scanning electron microscope and quantitative study. Anat Rec 1990; 228: 315–326.CrossRefPubMedGoogle Scholar
  18. 18.
    Haddon CH, Lewis JH. Early ear development in the embryo of the zebrafish, Danio rerio. J Comp Neurol 1996; 365: 113–128.CrossRefPubMedGoogle Scholar
  19. 19.
    Anniko M. Postnatal maturation of cochlear sensory hairs in the mouse. Anat Embryol 1983; 166: 355–368.CrossRefPubMedGoogle Scholar
  20. 20.
    Hemond SG, Morest DK. Ganglion formation from the otic placode and the otic crest in the chick embryo: Mitosis, migration and the basal lamina. Anat Embryol 1991; 184: 1–13.PubMedGoogle Scholar
  21. 21.
    D’Amico Martel A, Noden MD. Contribution of placodial and neural crest cells to avian cranial peripheral ganglia. Am J Anat 1983; 166: 445–468.PubMedGoogle Scholar
  22. 22.
    Bever MM, Fekete DM. Ventromedial focus of cell death in absent during development of Xenopus and zebrafish inner ears. J Neurocytol 1999; 28: 781–793.PubMedGoogle Scholar
  23. 23.
    Popper AN, Platt C, Edds PL. Evolution of the vertebreate inner ears. J Neurocytol 1999; 28: 781–793.PubMedGoogle Scholar
  24. 23.
    Popper AN, Platt C, Edds PL. Evolution of the vertebrate inner ear: An overviewof ideas. In: Webster DB, Fay RR, Popper AN, eds. The Evolutionary Biology of Hearing. New York: Springer-Verlag 1992: 49–57.Google Scholar
  25. 24.
    Lewis ER. Convergence of design in vertebrate acoustic sensor. In: Webster DB, Fay RR, Popper AN, eds. The Evolutionary Biology of Hearing. New York: Springer-Verlag 1992: 163–184.Google Scholar
  26. 25.
    Sanz C, León Y, Cañón S, Alvarez L, Giraldez F, Varela-Nieto I. Patter of expression of the Jun family of transcription factors during the early development of the inner ear: Implications in apoptosis. J Cell Sci 1999; 112: 3967–3974.PubMedGoogle Scholar
  27. 26.
    Lang H, Bever MM, Fekete DM. Cell proliferation and cell death in the developing chick inner ear: Spatial and temporal patterns. J Comp Neurol 2000; 417: 205–220.PubMedGoogle Scholar
  28. 27.
    Nikolic P, Järlebark LE, Billett TE, Thorne Pr. Apoptosis in the developing rat cochlea and its related structures. Dev Brain Res 2000; 119: 75–83.Google Scholar
  29. 28.
    Fekete DM, Homburger SA, Waring MT, Riedl AE, Garcia LF. Involvement of programmedcell death in morphogenesis of the vertebrate inner ear. Development 1997; 124: 2451–2461.PubMedGoogle Scholar
  30. 29.
    Nishizaki K, Anniko M, Orita Y, Masuda Y, Yoshino T. Programmed cell death in the mouse cochleovestibular ganglion during development. ORL J Otorhinolaryngol Relat Spec 1998; 60: 267–271.PubMedGoogle Scholar
  31. 30.
    Represa JJ, Moro JA, Pastor F, Gato A, Barbosa E. PPaterns of epithelial cell death during early development of the human inner ear. Ann Oto Rhinol Laryn 1990; 99: 482–488.Google Scholar
  32. 31.
    Marovitz WF, Khan KM, Schultev T. Ultrastructural development of the early rat otocyst. Ann Otol Rhinol Laryngol Suppl 1977; 86: 9–28.PubMedGoogle Scholar
  33. 32.
    Marovitz WF, Shugar JM, Khan KM. The role of cellular degeneration in the normal development of rat otocyst. Laryngoscope 1976; 86: 1413–1425.PubMedGoogle Scholar
  34. 33.
    Nishizaki K, Anniko M, Orita Y, Karita K, Masuda Y, Yoshino T. Programmed cell death in the developing epithelium of the mouse inner ear. Acta Otolaryngol (Stockh) 1998; 118: 96–100.Google Scholar
  35. 34.
    Zheng JL, Gao W-Q. Analysis of rat vestibular hair cell development and regeneration using calretinin as an early marker. J Neurosci 1997; 17: 8270–8282.PubMedGoogle Scholar
  36. 35.
    Hemond SG, Morest DK. Tropic effects of otic epithelium on cochleo-vestibular ganglion fiber growth in vitro. The Anat Rec 1992; 232: 273–284.Google Scholar
  37. 36.
    Fekete DM, Muthukumar S, Karagogeos D. Hair cells and supporting cells share a common progenitor in the avian inner ear. J Neurosci 1998; 18: 7811–7821.PubMedGoogle Scholar
  38. 37.
    Cotanche DA, Lee KH. Regeneration of hair cells in the vestibulocochlear system of birds and mammals. Curr Opin Neurobiol 1994; 4: 509–514.PubMedGoogle Scholar
  39. 38.
    Roberson DF, Weisleder P, Bohrer P, Rubel EW. Ongoing production of sensory cells in the vestibular epithelium of the chick. Hear Res 1992; 57: 166–174.PubMedGoogle Scholar
  40. 39.
    Kil J, Warchol M, Corwin J. Cell death, cell proliferation and estimates of hair cell life spans in the vestibular organs of chicks. Hear Res 1997; 114: 117–126.PubMedGoogle Scholar
  41. 40.
    Weisleder P, Tsue TT, Rubel EW. Hair cell replacement in avian vestibular epithelium: Supporting cell to type I hair cell. Hear Res 1995; 82: 125–133.PubMedGoogle Scholar
  42. 41.
    Adler HJ, Raphael Y. New hair cells arise from supporting cell conversion in the acoustically damaged chick inner ear. Neurosci Lett 1996; 205: 17–20.PubMedGoogle Scholar
  43. 42.
    Warchol ME, Corwin JT. Regenerative proliferation in organ cultures of the avian cochlea: identification of the initial progenitors and determination of thelatency of the proliferative response. J Neurosci 1996; 16: 5466–5477.PubMedGoogle Scholar
  44. 43.
    Corwin J. Postembryonic production and aging inner ear cells in sharks. J Comp Neurol 1981; 201: 541–553.PubMedGoogle Scholar
  45. 44.
    Williams JA, Holder N. Cell turnover in neuromasts of zebrafish larvae. Hear Res 2000; 143: 171–181.PubMedGoogle Scholar
  46. 45.
    Corwin JT. Perpetual production of hair cells and maturational changes in hair cells ultrstructure accompany postembryonic growth in an amphibian ear. Proc Natl Acad Sci USA 1985; 82: 3911–3915.PubMedGoogle Scholar
  47. 46.
    Baird RA, Steyger PS, Schuff NR. Mitotic and nonmitotic hair cell regeneration in the bullfrog vestibular otolith organs. Ann NY Acad Sci 1996; 781: 59–70.PubMedGoogle Scholar
  48. 47.
    Forge A, Li L, Corwin JT, Nevill G. Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 1993; 259: 1616–1619.PubMedGoogle Scholar
  49. 48.
    Warchol ME, Lambert PR, Goldstein BJ, Forge A, Corwin JT. Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 1993; 259: 1619–1622.PubMedGoogle Scholar
  50. 49.
    Forge A, Li L, Nevill G. Hair cell recovery in the vestibular sensory epithelia of mature guinea pigs. J Comp Neurol 1998; 397: 69–88.PubMedGoogle Scholar
  51. 50.
    Kirkegaard M. Jørgensen JM. The inner ear macular sensory epithelia of the Daubenton’s bat. J Comp Neurol 2001; 438: 433–444.PubMedGoogle Scholar
  52. 51.
    Li H, Roblin G, Liu H, Heller S. Generation of hair cells by stepwise differentiation of embryonic stem cells. Proc Natl Acad Sci USA 2003; 100: 13495–13500.PubMedGoogle Scholar
  53. 52.
    Haddon CH, Lewis JH. Hyaluronan as a propellant for epithelial movement: The development of semicircular canals in the inner ear of Xenopus. Development 1991; 112: 541–550.PubMedGoogle Scholar
  54. 53.
    Waterman RE, Bell DH. Epithelial fusion during early semicircular canal formation in the embryonic zebrafish. Brachydanio Rerio Anat Rec 1984; 210: 101–114.Google Scholar
  55. 54.
    Martin P, Swanson GJ. Descriptive and experimental analysis of the epithelial remodelings that control semicircular canal formation in the developing mouse inner ear. Dev Biol 1993; 159: 1–10.PubMedGoogle Scholar
  56. 55.
    D’Amico-Martel A. Temporal patterns of neurogenesis in avian cranial sensory and autonomic ganglia. Am J Anat 1982; 163: 351–372.PubMedGoogle Scholar
  57. 56.
    Ard MD, Morest DK. Cell death during development of the cochlear and vestibular ganglia of the chick. Int J Dev Neurosci 1984; 2: 535–547.Google Scholar
  58. 57.
    Altman F. Normal development of the ear and its mechanics. Arch Otolaryngol 1950; 52: 725–766.Google Scholar
  59. 58.
    Pullan S, Willson J, Metclafe A, et al. requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. J Cell Sci 1996; 109: 631–642.PubMedGoogle Scholar
  60. 59.
    Rueda J, de la Sen C, Juiz JM, Merchan JA. Neuronal loss in the spiral ganglion of young rats. Acta Otolaryngol 1987; 104: 417–421.PubMedGoogle Scholar
  61. 60.
    Kamiya K, Takahashi K, Kitamura K, Momoi T, Yoshikawa Y. Mitosis and apoptosis in postnatal auditory system of the C3H/He strain. Brain Res 2001; 901: 296–302.PubMedGoogle Scholar
  62. 61.
    Jókay I, Soós G, Répássy G, Dezsõ B. Apoptosis in the human inner ear. Detection by in situ end-labeling of fragmented DNA and correlation with other markers. Hear Rest 1998; 117: 131–139.Google Scholar
  63. 62.
    De la Rosa EJ, De Pablo F. Cell death in early neural development: Beyond the neurotrophic theory. Trends Neurosci 2000; 23: 454–458.PubMedGoogle Scholar
  64. 63.
    Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: Lessons from the nervous system. Science 1993; 262: 695–700.PubMedGoogle Scholar
  65. 64.
    Varela-Nieto I, De la Rose EJ, Valenciano AI, León Y. Cell death in the nervous system: Lessons from insulin and insulin-like growth factors. Mol Neurobiol 2003; 28: 23–49.PubMedGoogle Scholar
  66. 65.
    Davies AM. Regulation of neuronal survival and death by extracellular signals during development. EMBO J 2003; 22: 2537–2545.PubMedGoogle Scholar
  67. 66.
    León Y. Vázquez E, Sanz C, et al. Insulin-like growth factor-I regulates cell proliferation in the developing inner ear by activation of glycosil-phosphatidylinositol hydrolysis and Fos expression. Endocrinol 1995; 136: 3494–3503.Google Scholar
  68. 67.
    León Y, Sanz C, Giráldez F, Varela-Nieto I. Induction of cell growth by insulin and insulin-like growth factor-I is associated with Jun expression in the otic vesicle. J Comp Neurol 1998; 398: 323–332.PubMedGoogle Scholar
  69. 68.
    Camarero G, León Y, Gorospe I, et al. Insulin-like growth factor 1 is required for survival of transit-amplifying neuroblasts and differentiation of otic neurons. Dev Biol 2003; 262: 242–253.PubMedGoogle Scholar
  70. 69.
    Frago LM, León Y, De la Rosa EJ, Gómez-MÚñoz A, Varela-Nieto I. Nerve growth factor and ceramides modulate cell death in the early developing inner ear. J Cell Sci 1998; 111: 549–556.PubMedGoogle Scholar
  71. 70.
    Frago LM, Cañón S, De la Rosa EJ, León Y, Varela-Nieto I. Programmed cell death in the developing inner ear is balanced by nerve growth factor and insulin-like growth factor I. J Cell Sci 2003; 116: 475–486.PubMedGoogle Scholar
  72. 71.
    Sanz C, León Y, Troppmair J, Rapp UR, Varela-Nieto I. Strict regulation of c-Raf kinase levels is required for early organo-genesis of the vertebrate inner ear. Oncogene 1999; 18: 429–437.PubMedGoogle Scholar
  73. 72.
    Frago LM, Camarero G, Cañón S, et al. Role of diffusible and transcriptional factors in inner ear development: Implications in regeneration. Histol Histopathol 2000; 15: 657–666.PubMedGoogle Scholar
  74. 73.
    Kopke RD, Jackson RL, Li G, et al. Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function. Proc Natl Acad Sci USA 2001; 98: 5886–5891.PubMedGoogle Scholar
  75. 74.
    Oesterle EC, Tsue TT, Rubel EW. Induction of cell proliferation in avian inner ear sensory epithelia by insulin-like growth factor-I and insulin. J Comp Neurol 1997; 380: 262–274.PubMedGoogle Scholar
  76. 75.
    Camarero G, Avendaño C, Fernández-Moreno C, et al. Delayed inner ear maturation and neuronal lossin postnatal Igf-1-deficient mice. J Neurosci 2001; 21: 7630–7641.PubMedGoogle Scholar
  77. 76.
    Camarero G, Villar MA, Contreras J, et al. Cochlear abnormalities in insulin-like growth factor-1 mouse mutants. Hear Res 2002; 170: 2–11.PubMedGoogle Scholar
  78. 77.
    Von Bartheld CS, Patterson SL, Heuer JG, Wheeler EF, Bothwell M, Rubel EW. Expression of nerve growth factor receptors in the developing inner ear of chick and rat. Development 1991; 113: 455–470.PubMedGoogle Scholar
  79. 78.
    Van Blitterswijk WJ, van der Luit AH, Veldman RJ, Verheij M, Borst J. Ceramide: Second messenger or modulator of membrane structure and dynamics? Biochem J 2003; 369: 199–211.PubMedGoogle Scholar
  80. 79.
    Avila MA, Varela-Nieto I, Romero G, et al. Brain-derived neurotrophic factor and neurotrophin-3 support the survival and neuritogenesis response of developing cochleovestibular ganglion neurons. Dev Biol 1993; 159: 266–275.PubMedGoogle Scholar
  81. 80.
    Represa J, Avila MA, Romero G, Mato JM, Giraldez F, Varela-Nieto I. Brain-derived neurotrophic factor and neurotrophin-3 induce cel proliferation in the cochleovestibular ganglion through a glycosyl-phosphatidylinositol signaling system. Dev Biol 1993; 159: 275–265.Google Scholar
  82. 81.
    Staecker H, Gabaizadeh R, Federoff H, Van de Water TR. Brain-derived neurotrophic factor gene therapy prevents spiral ganglion degeneration after hair cell loss. Otolaryngol H N Surg 1998; 119: 7–13.Google Scholar
  83. 82.
    Fritzsch B, Pirvola U, Ylikoski J, Making and breaking the innervation of the ear: Neurotrophic support during ear development and its clinical implications. Cell Tissue Res 1999; 296: 369–382.Google Scholar
  84. 83.
    Merry DE, Korsmeyer SJ, Bcl-2 gene family in the nervous system. Annu Rev Neurosci. 1997; 20: 245–267.PubMedGoogle Scholar
  85. 84.
    Ishii N, Wanaka A, Ohno K, et al. Localization of bcl-2, bax, and bcl-x mRNA in the developing inner ear of the mouse. Brain Res 1996; 726: 123–128.PubMedGoogle Scholar
  86. 85.
    Mostafapour SP, Del Puerto NM, Rubel EW. Bcl-2 overexpression eliminates deprivation-induced cell death of brainstem auditory neurons. J Neurosci 2002; 22: 4670–4674.PubMedGoogle Scholar
  87. 86.
    Kuan CY, Roth KA, Flavell RA, Rakic P. Mechanisms of programmed cell death in the developing brain. Trends Neurosci 2000; 23: 291–297.PubMedGoogle Scholar
  88. 87.
    Strasser A, O’Connor L, Dixit VM. Apoptosis signaling. Ann Rev Biochem 2000; 69: 217–245.PubMedGoogle Scholar
  89. 88.
    Nakagawa T, Kim TS, Murai N, et al. A novel technique for inducing local inner ear damage. Hear Res 2003; 176: 122–127.PubMedGoogle Scholar
  90. 89.
    Barinaga M. Death by dozens of cuts. Science 1998; 280; 32–34.PubMedGoogle Scholar
  91. 90.
    Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281: 1312–1316.PubMedGoogle Scholar
  92. 91.
    Takahashi K, Kamiya K, Urase K, et al. Caspase-3–deficiency induces hyperplasia of supporting cells and degeneration of sensory cells resulting in the hearing loss. Brain Res 2001; 894: 359–367.PubMedGoogle Scholar
  93. 92.
    Morishita H, Makishima T, Kaneko C, et al. Deafness due to degeneration of cochlear neurons in caspase-3–deficient mice. Biochem Biophys Res Comm 2001; 284: 142–149.PubMedGoogle Scholar
  94. 93.
    Yabu T, Kishi S, Okazaki T, Yamashita M. Characterization of zebrafish caspase-3 and induction of apoptosis through ceramide generation in fish fathead minnow tailbud cells and zebrafish embryo. Biochem J 2001; 360: 39–47.PubMedGoogle Scholar
  95. 94.
    Yamashita M. Apoptosis in zebrafish development. Comp Biochem Physiol B 2003; 136: 731–742.PubMedGoogle Scholar
  96. 95.
    Varela-Nieto I, Morales-Garcia JA, Vigil P, et al. Trophic effects of insulin-like growth factor-I (IGF-I) in the inner ear. Hear Res 2004; (in press).Google Scholar
  97. 96.
    Bhaker AL, Howell JL, Paul CE, et al. Apoptosis induced by p75NTR overexpression requires Jun kinase-dependent phosphorylation of Bad. J Neurosci 2003; 23: 11373–11381.PubMedGoogle Scholar
  98. 97.
    Ylikoski J, Xing-Qun L, Virkkala J, Pirvola U. Blockade of c-Jun N-terminal kinase pathway attenuates gentamicin-induced cochlear and vestibular hair cel death. Hear Res 2002;163: 71–81.PubMedGoogle Scholar
  99. 98.
    Hamburger V, Hamilton H. A series of normal stages in the development of the chick embryo. J Morphol 1951; 88: 49–92.CrossRefGoogle Scholar
  100. 99.
    León Y, Sanz C, Frago LM, et al. Involvement of insulin-like growth factor-I in inner ear organogenesis and regeneration. Horm Metab Res 1999; 31: 126–132.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  1. 1.Instituto de Investigaciones Biomédicas “Alberto Sols”Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)MadridSpain;
  2. 2.Departamento de BiologíaUnidad de Fisiología Animal, UAMMadridSpain

Personalised recommendations