Morphogenetic Mechanisms of Inner Ear Development



The vertebrate inner ear is one of the most complex three-dimensional sense organs of our head. This anatomical complexity reflects its different functions as the organ responsible for the senses of hearing and balance: it detects the direction and speed of head rotation and the wide range of sound wave frequencies. During embryonic development, specialized cells (hair cells ) originate in distinct domains of the inner ear , the sensory patches, whose topological organisation and orientation is fundamental for proper sensory function. Hair cells have the ability to convert mechanical stimuli into electrical activity that is then transmitted to the brain by sensory neurons. The major sensory patches comprise the three cristae (for angular movement detection), the saccule and utricule (for gravity detection) and the auditory sensory patch, the organ of Corti in mammals or basilar papilla in birds (for auditory detection). For sensory cells to be born in appropriate locations, inner ear patterning and cell fate specification must be coupled with morphogenesis of the entire organ. While excellent reviews have summarized the pathways involved in inner ear patterning (Fekete in Curr Opin Neurobiol 6(4):533–541, 1996; Whitfield et al. in Off Publ Am Assoc Anat 223(4):427–458, 2002; Torres and Giráldez in Mech Dev 71(1–2):5–21, 1998; Fekete and Wu in Curr Opin Neurobiol 12(1):35–42, 2002; Barald and Kelley in Development (Cambridge, England), 131(17):4119–4130, 2004; Alsina et al. in Int J Dev Biol 53(8–10):1503–1513, 2009) morphogenetic events have received little attention and in particular the cross-talk between patterning and morphogenetic cues is poorly understood. In this chapter we will review the morphogenetic mechanisms regulating inner ear shape, size and sensory organization. A wide array of cell behaviours contributes to the final size and shape of all organs. These include cell migration, modulation of cell division or cell death, oriented cell division, epithelial to mesenchymal transition, cell intercalation and remodelling and convergent extension movements. Many of these operate in the inner ear and we will review how each contributes to sculpting the inner ear into its final form.


Inner ear Otocyst Hair cells Cochlea Invagination Placode PCP Lumen formation Pax2 Stereocilia Convergent extension 


  1. Abello, G., & Alsina, B. (2007). Establishment of a proneural field in the inner ear. The International Journal of Developmental Biology, 51(6–7), 483–493.PubMedCrossRefGoogle Scholar
  2. Alsina, B., Giraldez, F., & Pujades, C. (2009). Patterning and cell fate in ear development. The International Journal of Developmental Biology, 53(8–10), 1503–1513.PubMedCrossRefGoogle Scholar
  3. Alvarez, I. S., & Navascués, J. (1990). Shaping, invagination, and closure of the chick embryo otic vesicle: Scanning electron microscopic and quantitative study. The Anatomical Record, 228(3), 315–326.PubMedCrossRefGoogle Scholar
  4. Alvarez, I. S., et al. (1989). Cell proliferation during early development of the chick embryo otic anlage: Quantitative comparison of migratory and nonmigratory regions of the otic epithelium. The Journal of Comparative Neurology, 290(2), 278–288.PubMedCrossRefGoogle Scholar
  5. Andreeva, A., et al. (2014). PTK7-Src signaling at epithelial cell contacts mediates spatial organization of actomyosin and planar cell polarity. Developmental Cell, 29(1), 20–33.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ashery-Padan, R., & Gruss, P. (2001). Pax6 lights-up the way for eye development. Current Opinion in Cell Biology, 13(6), 706–714.PubMedCrossRefGoogle Scholar
  7. Ashery-Padan, R., et al. (2000). Pax6 activity in the lens primordium is required for lens formation and for correct placement of a single retina in the eye. Genes & Development, 14(21), 2701–2711.CrossRefGoogle Scholar
  8. Babb-Clendenon, S., et al. (2006). Cadherin-2 participates in the morphogenesis of the zebrafish inner ear. Journal of Cell Science, 119(Pt 24), 5169–5177.PubMedCrossRefGoogle Scholar
  9. Bancroft, M., & Bellairs, R. (1977). Placodes of the chick embryo studied by SEM. Anatomy and Embryology, 151(1), 97–108.PubMedCrossRefGoogle Scholar
  10. Barald, K. F., & Kelley, M. W. (2004). From placode to polarization: New tunes in inner ear development. Development (Cambridge, England), 131(17), 4119–4130.CrossRefGoogle Scholar
  11. Barembaum, M., & Bronner-Fraser, M. (2007). Spalt4 mediates invagination and otic placode gene expression in cranial ectoderm. Development (Cambridge, England), 134(21), 3805–3814.CrossRefGoogle Scholar
  12. Barembaum, M., & Bronner-Fraser, M. (2010). Pax2 and Pea3 synergize to activate a novel regulatory enhancer for spalt4 in the developing ear. Developmental Biology, 340(2), 222–231.PubMedCrossRefGoogle Scholar
  13. Barrionuevo, F., et al. (2008). Sox9 is required for invagination of the otic placode in mice. Developmental Biology, 317(1), 213–224.PubMedCrossRefGoogle Scholar
  14. Bhat, N., & Riley, B. B. (2011). Integrin-α5 coordinates assembly of posterior cranial placodes in zebrafish and enhances Fgf-dependent regulation of otic/epibranchial cells. PLoS ONE, 6(12), e27778.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bhattacharyya, S., & Bronner, M. E. (2013). Clonal analyses in the anterior pre-placodal region: Implications for the early lineage bias of placodal progenitors. The International Journal of Developmental Biology, 57(9–10), 753–757.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bissonnette, J. P., & Fekete, D. M. (1996). Standard atlas of the gross anatomy of the developing inner ear of the chicken. The Journal of Comparative Neurology, 368(4), 620–630.PubMedCrossRefGoogle Scholar
  17. Bok, J., et al. (2013). Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells. Proceedings of the National Academy of Sciences of the United States of America, 110(34), 13869–13874.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Borges, R. M., et al. (2011). Rho signaling pathway and apical constriction in the early lens placode. Genesis (New York, N.Y.: 2000), 49(5), 368–379.CrossRefGoogle Scholar
  19. Breau, M. A., & Schneider-Maunoury, S. (2014). Cranial placodes: Models for exploring the multi-facets of cell adhesion in epithelial rearrangement, collective migration and neuronal movements. Developmental Biology.Google Scholar
  20. Castanon, I., & González-Gaitán, M. (2011). Oriented cell division in vertebrate embryogenesis. Current Opinion in Cell Biology, 23(6), 697–704.PubMedCrossRefGoogle Scholar
  21. Chacon-Heszele, M. F., et al. (2012). Regulation of cochlear convergent extension by the vertebrate planar cell polarity pathway is dependent on p120-catenin. Development (Cambridge, England), 139(5), 968–978.CrossRefGoogle Scholar
  22. Chang, W., ten Dijke, P., & Wu, D. K. (2002). BMP pathways are involved in otic capsule formation and epithelial-mesenchymal signaling in the developing chicken inner ear. Developmental Biology, 251(2), 380–394.PubMedCrossRefGoogle Scholar
  23. Chang, W., et al. (2004). The development of semicircular canals in the inner ear: Role of FGFs in sensory cristae. Development (Cambridge, England), 131(17), 4201–4211.CrossRefGoogle Scholar
  24. Chauhan, B. K., et al. (2011). Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia. Proceedings of the National Academy of Sciences of the United States of America, 108(45), 18289–18294.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Chen, J., & Streit, A. (2013). Induction of the inner ear: Stepwise specification of otic fate from multipotent progenitors. Hearing Research, 297, 3–12.CrossRefPubMedGoogle Scholar
  26. Chen, P., et al. (2002). The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development (Cambridge, England), 129(10), 2495–2505.Google Scholar
  27. Chen, W.-S., et al. (2008). Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling. Cell, 133(6), 1093–1105.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Choo, D., et al. (2006). Molecular mechanisms underlying inner ear patterning defects in kreisler mutants. Developmental Biology, 289(2), 308–317.PubMedCrossRefGoogle Scholar
  29. Christophorou, N. A. D., et al. (2010). Pax2 coordinates epithelial morphogenesis and cell fate in the inner ear. Developmental Biology, 345(2), 180–190.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Concha, M. L., & Adams, R. J. (1998). Oriented cell divisions and cellular morphogenesis in the zebrafish gastrula and neurula: A time-lapse analysis. Development (Cambridge, England), 125(6), 983–994.Google Scholar
  31. Cotanche, D. A., & Corwin, J. T. (1991). Stereociliary bundles reorient during hair cell development and regeneration in the chick cochlea. Hearing Research, 52(2), 379–402.PubMedCrossRefGoogle Scholar
  32. Curtin, J. A., et al. (2003). Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Current Biology: CB, 13(13), 1129–1133.PubMedCrossRefGoogle Scholar
  33. Dabdoub, A., et al. (2003). Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea. Development (Cambridge, England), 130(11), 2375–2384.CrossRefGoogle Scholar
  34. Das, D., et al. (2014). The interaction between Shroom3 and Rho-kinase is required for neural tube morphogenesis in mice. Biology Open, 3(9), 850–860.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Deans, M. R., et al. (2007). Asymmetric distribution of prickle-like 2 reveals an early underlying polarization of vestibular sensory epithelia in the inner ear. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 27(12), 3139–3147.CrossRefGoogle Scholar
  36. Etheridge, S. L., et al. (2008). Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development. PLoS Genetics, 4(11), e1000259.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Fekete, D. M. (1996). Cell fate specification in the inner ear. Current Opinion in Neurobiology, 6(4), 533–541.PubMedCrossRefGoogle Scholar
  38. Fekete, D. M., & Wu, D. K. (2002). Revisiting cell fate specification in the inner ear. Current Opinion in Neurobiology, 12(1), 35–42.PubMedCrossRefGoogle Scholar
  39. Fekete, D. M., et al. (1997). Involvement of programmed cell death in morphogenesis of the vertebrate inner ear. Development (Cambridge, England), 124(12), 2451–2461.Google Scholar
  40. Freter, S., et al. (2008). Progressive restriction of otic fate: The role of FGF and Wnt in resolving inner ear potential. Development (Cambridge, England), 135(20), 3415–3424.CrossRefGoogle Scholar
  41. Freter, S., et al. (2012). Pax2 modulates proliferation during specification of the otic and epibranchial placodes. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 241(11), 1716–1728.CrossRefGoogle Scholar
  42. Geng, F.-S., et al. (2013). Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene. Development (Cambridge, England), 140(21), 4362–4374.CrossRefGoogle Scholar
  43. Gong, Y., Mo, C., & Fraser, S. E. (2004). Planar cell polarity signalling controls cell division orientation during zebrafish gastrulation. Nature, 430(7000), 689–693.PubMedCrossRefGoogle Scholar
  44. Goodrich, L. V., & Strutt, D. (2011). Principles of planar polarity in animal development. Development (Cambridge, England), 138(10), 1877–1892.CrossRefGoogle Scholar
  45. Goto, T., & Keller, R. (2002). The planar cell polarity gene strabismus regulates convergence and extension and neural fold closure in Xenopus. Developmental Biology, 247(1), 165–181.PubMedCrossRefGoogle Scholar
  46. Gubb, D., & García-Bellido, A. (1982). A genetic analysis of the determination of cuticular polarity during development in Drosophila melanogaster. Journal of Embryology and Experimental Morphology, 68, 37–57.PubMedGoogle Scholar
  47. Haddon, C., & Lewis, J. (1996). Early ear development in the embryo of the zebrafish, Danio rerio. The Journal of Comparative Neurology, 365(1), 113–128.PubMedCrossRefGoogle Scholar
  48. Haigo, S. L., et al. (2003). Shroom induces apical constriction and is required for hingepoint formation during neural tube closure. Current Biology: CB, 13(24), 2125–2137.PubMedCrossRefGoogle Scholar
  49. Hammond, K. L., et al. (2009). A late role for bmp2b in the morphogenesis of semicircular canal ducts in the zebrafish inner ear. PLoS ONE, 4(2), e4368.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Hans, S., Liu, D., & Westerfield, M. (2004). Pax8 and Pax2a function synergistically in otic specification, downstream of the Foxi1 and Dlx3b transcription factors. Development (Cambridge, England), 131(20), 5091–5102.CrossRefGoogle Scholar
  51. Hatch, E. P., et al. (2007). Fgf3 is required for dorsal patterning and morphogenesis of the inner ear epithelium. Development (Cambridge, England), 134(20), 3615–3625.CrossRefGoogle Scholar
  52. Haugas, M., et al. (2010). Gata2 is required for the development of inner ear semicircular ducts and the surrounding perilymphatic space. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 239(9), 2452–2469.CrossRefGoogle Scholar
  53. Heisenberg, C. P., et al. (2000). Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature, 405(6782), 76–81.PubMedCrossRefGoogle Scholar
  54. Hendrix, R. W., & Zwaan, J. (1974a). Cell shape regulation and cell cycle in embryonic lens cells. Nature, 247(5437), 145–147.PubMedCrossRefGoogle Scholar
  55. Hendrix, R. W., & Zwaan, J. (1974b). Changes in the glycoprotein concentration of the extracellular matrix between lens and optic vesicle associated with early lens differentiation. Differentiation; Research in Biological Diversity, 2(6), 357–362. Available at: Accessed March 29, 2015.
  56. Hilfer, S. R., Esteves, R. A., & Sanzo, J. F. (1989). Invagination of the otic placode: Normal development and experimental manipulation. Journal of Experimental Zoology, 251(2), 253–264.PubMedCrossRefGoogle Scholar
  57. Hilfer, S. R., & Randolph, G. J. (1993). Immunolocalization of basal lamina components during development of chick otic and optic primordia. The Anatomical Record, 235(3), 443–452.PubMedCrossRefGoogle Scholar
  58. Höckendorf, B., Thumberger, T., & Wittbrodt, J. (2012). Quantitative analysis of embryogenesis: A perspective for light sheet microscopy. Developmental Cell, 23(6), 1111–1120.PubMedCrossRefGoogle Scholar
  59. Hoijman, E., et al. (2015). Mitotic cell rounding and epithelial thinning regulate lumen growth and shape. Nature Communications, 6, 7355–7367.PubMedCrossRefGoogle Scholar
  60. Huang, J., et al. (2011). The mechanism of lens placode formation: A case of matrix-mediated morphogenesis. Developmental Biology, 355(1), 32–42.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Huisken, J., & Stainier, D. Y. R. (2009). Selective plane illumination microscopy techniques in developmental biology. Development (Cambridge, England), 136(12), 1963–1975.CrossRefGoogle Scholar
  62. Hultcrantz, M., Bagger-Sjöbäck, D., & Rask-Andersen, H. (1987). The development of the endolymphatic duct and sac. A light microscopical study. Acta Oto-laryngologica, 104(5–6), 406–416.PubMedCrossRefGoogle Scholar
  63. Iruela-Arispe, M. L., & Beitel, G. J. (2013). Tubulogenesis. Development, 140(14), 2851–2855.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Jessen, J. R., et al. (2002). Zebrafish trilobite identifies new roles for Strabismus in gastrulation and neuronal movements. Nature Cell Biology, 4(8), 610–615.PubMedPubMedCentralGoogle Scholar
  65. Jones, C., & Chen, P. (2007). Planar cell polarity signaling in vertebrates. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 29(2), 120–132.CrossRefGoogle Scholar
  66. Jones, C., et al. (2008). Ciliary proteins link basal body polarization to planar cell polarity regulation. Nature Genetics, 40(1), 69–77.PubMedCrossRefGoogle Scholar
  67. Jones, C., et al. (2014). Ankrd6 is a mammalian functional homolog of Drosophila planar cell polarity gene diego and regulates coordinated cellular orientation in the mouse inner ear. Developmental Biology, 395(1), 62–72.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Kelley, M. W. (2006). Regulation of cell fate in the sensory epithelia of the inner ear. Nature Reviews Neuroscience, 7(11), 837–849.PubMedCrossRefGoogle Scholar
  69. Kibar, Z., et al. (2011). Contribution of VANGL2 mutations to isolated neural tube defects. Clinical Genetics, 80(1), 76–82.PubMedCrossRefGoogle Scholar
  70. Kim, H. Y., & Davidson, L. A. (2011). Punctuated actin contractions during convergent extension and their permissive regulation by the non-canonical Wnt-signaling pathway. Journal of Cell Science, 124(Pt 4), 635–646.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Koehler, K. R., & Hashino, E. (2014). 3D mouse embryonic stem cell culture for generating inner ear organoids. Nature Protocols, 9(6), 1229–1244.PubMedCrossRefGoogle Scholar
  72. Lang, H., Bever, M. M., & Fekete, D. M. (2000). Cell proliferation and cell death in the developing chick inner ear: Spatial and temporal patterns. The Journal of Comparative Neurology, 417(2), 205–220.PubMedCrossRefGoogle Scholar
  73. Lang, R. A., et al. (2014). p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis. Development (Cambridge, England), 141(16), 3177–3187.CrossRefGoogle Scholar
  74. Lecuit, T., & Lenne, P. F. (2007). Cell surface mechanics and the control of cell shape, tissue patterns and morphogenesis. Nature Review Molecular Cell Biology, 8(8), 633–44.Google Scholar
  75. Lilleväli, K., et al. (2006). Gata3 is required for early morphogenesis and Fgf10 expression during otic development. Mechanisms of Development, 123(6), 415–429.PubMedCrossRefGoogle Scholar
  76. Lin, Z., et al. (2005). Gbx2 is required for the morphogenesis of the mouse inner ear: A downstream candidate of hindbrain signaling. Development (Cambridge, England), 132(10), 2309–2318.CrossRefGoogle Scholar
  77. López-Schier, H., & Hudspeth, A. J. (2006). A two-step mechanism underlies the planar polarization of regenerating sensory hair cells. Proceedings of the National Academy of Sciences of the United States of America, 103(49), 18615–18620.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Lu, X., et al. (2004). PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature, 430(6995), 93–98.PubMedCrossRefGoogle Scholar
  79. Mansour, S. L., Goddard, J. M., & Capecchi, M. R. (1993). Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. Development (Cambridge, England), 117(1), 13–28.Google Scholar
  80. Mansour, S., & Schoenwolf, G. (2005). Morphogenesis of the inner ear. In R. R. M. W. Wu (Ed.), The Springer handbook of auditory research (pp. 43–84). New York: Springer.Google Scholar
  81. Martin, P., & Swanson, G. J. (1993). Descriptive and experimental analysis of the epithelial remodellings that control semicircular canal formation in the developing mouse inner ear. Developmental Biology, 159(2), 549–558.PubMedCrossRefGoogle Scholar
  82. Matsumata, M., et al. (2005). Multiple N-cadherin enhancers identified by systematic functional screening indicate its Group B1 SOX-dependent regulation in neural and placodal development. Developmental Biology, 286(2), 601–617.PubMedCrossRefGoogle Scholar
  83. May-Simera, H. L., et al. (2010). Bbs8, together with the planar cell polarity protein Vangl2, is required to establish left-right asymmetry in zebrafish. Developmental Biology, 345(2), 215–225.PubMedCrossRefGoogle Scholar
  84. May-Simera, H. L., et al. (2015). Ciliary proteins Bbs8 and Ift20 promote planar cell polarity in the cochlea. Development, 142(3), 555–566.PubMedPubMedCentralCrossRefGoogle Scholar
  85. McCarroll, M. N., et al. (2012). Graded levels of Pax2a and Pax8 regulate cell differentiation during sensory placode formation. Development (Cambridge, England), 139(15), 2740–2750.CrossRefGoogle Scholar
  86. McGreevy, E. M., et al. (2015). Shroom3 functions downstream of planar cell polarity to regulate myosin II distribution and cellular organization during neural tube closure. Biology Open, 4(2), 186–196.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Meier, S. (1978a). Development of the embryonic chick otic placode. I. Light microscopic analysis. The Anatomical Record, 191(4), 447–458.PubMedCrossRefGoogle Scholar
  88. Meier, S. (1978b). Development of the embryonic chick otic placode. II. Electron microscopic analysis. The Anatomical Record, 191(4), 459–477.PubMedCrossRefGoogle Scholar
  89. Montcouquiol, M., et al. (2003). Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature, 423(6936), 173–177.PubMedCrossRefGoogle Scholar
  90. Montcouquiol, M., et al. (2006). Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 26(19), 5265–5275.CrossRefGoogle Scholar
  91. Moro-Balbás, J. A., et al. (2000). Basal lamina heparan sulphate proteoglycan is involved in otic placode invagination in chick embryos. Anatomy and Embryology, 202(4), 333–343.PubMedCrossRefGoogle Scholar
  92. Morsli, H., et al. (1998). Development of the mouse inner ear and origin of its sensory organs. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 18(9), 3327–3335.Google Scholar
  93. Muñoz-Espín, D., et al. (2013). Programmed cell senescence during mammalian embryonic development. Cell, 155(5), 1104–1118.PubMedCrossRefGoogle Scholar
  94. Nayak, G. D., et al. (2007). Development of the hair bundle and mechanotransduction. The International Journal of Developmental Biology, 51(6–7), 597–608.PubMedCrossRefGoogle Scholar
  95. Nichols, D. H., et al. (2008). Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis. Cell and Tissue Research, 334(3), 339–358.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Nishikori, T., et al. (1999). Apoptosis during inner ear development in human and mouse embryos: An analysis by computer-assisted three-dimensional reconstruction. Anatomy and Embryology, 200(1), 19–26.PubMedCrossRefGoogle Scholar
  97. Nishimura, T., Honda, H., & Takeichi, M. (2012). Planar cell polarity links axes of spatial dynamics in neural-tube closure. Cell, 149(5), 1084–1097.PubMedCrossRefGoogle Scholar
  98. Nishimura, T., & Takeichi, M. (2008). Shroom3-mediated recruitment of Rho kinases to the apical cell junctions regulates epithelial and neuroepithelial planar remodeling. Development (Cambridge, England), 135(8), 1493–1502.CrossRefGoogle Scholar
  99. Nishizaki, K., et al. (1998). Programmed cell death in the developing epithelium of the mouse inner ear. Acta Oto-Laryngologica, 118(1), 96–100.PubMedCrossRefGoogle Scholar
  100. Noda, T., et al. (2012). Restriction of Wnt signaling in the dorsal otocyst determines semicircular canal formation in the mouse embryo. Developmental Biology, 362(1), 83–93.PubMedCrossRefGoogle Scholar
  101. Ohta, S., Mansour, S. L., & Schoenwolf, G. C. (2010). BMP/SMAD signaling regulates the cell behaviors that drive the initial dorsal-specific regional morphogenesis of the otocyst. Developmental Biology, 347(2), 369–381.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Ohyama, T. (2006). Wnt signals mediate a fate decision between otic placode and epidermis. Development, 133(5), 865–875.PubMedCrossRefGoogle Scholar
  103. Ohyama, T., Groves, A. K., & Martin, K. (2007). The first steps towards hearing: Mechanisms of otic placode induction. The International Journal of Developmental Biology, 51(6–7), 463–472.PubMedCrossRefGoogle Scholar
  104. Ohyama, T., et al. (2010). BMP signaling is necessary for patterning the sensory and nonsensory regions of the developing mammalian cochlea. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30(45), 15044–15051.CrossRefGoogle Scholar
  105. Padanad, M. S., & Riley, B. B. (2011). Pax2/8 proteins coordinate sequential induction of otic and epibranchial placodes through differential regulation of foxi1, sox3 and fgf24. Developmental Biology, 351(1), 90–98.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Pasqualetti, M., et al. (2001). Retinoic acid rescues inner ear defects in Hoxa1 deficient mice. Nature Genetics, 29(1), 34–39.PubMedCrossRefGoogle Scholar
  107. Pauley, S., et al. (2003). Expression and function of FGF10 in mammalian inner ear development. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 227(2), 203–215.CrossRefGoogle Scholar
  108. Petit, C., Levilliers, J., & Hardelin, J. P. (2001). Molecular genetics of hearing loss. Annual Review of Genetics, 35, 589–646. Available at: Accessed March 29, 2015.
  109. Pieper, M., et al. (2011). Origin and segregation of cranial placodes in Xenopus laevis. Developmental Biology, 360(2), 257–275.PubMedCrossRefGoogle Scholar
  110. Pirvola, U., et al. (2000). FGF/FGFR-2(IIIb) signaling is essential for inner ear morphogenesis. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 20(16), 6125–6134.Google Scholar
  111. Plageman, T. F., et al. (2010). Pax6-dependent Shroom3 expression regulates apical constriction during lens placode invagination. Development (Cambridge, England), 137(3), 405–415.CrossRefGoogle Scholar
  112. Plageman, T. F., et al. (2011). A Trio-RhoA-Shroom3 pathway is required for apical constriction and epithelial invagination. Development (Cambridge, England), 138(23), 5177–5188.PubMedCentralCrossRefGoogle Scholar
  113. Qian, D., et al. (2007). Wnt5a functions in planar cell polarity regulation in mice. Developmental Biology, 306(1), 121–133.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Rakowiecki, S., & Epstein, D. J. (2013). Divergent roles for Wnt/β-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. Development (Cambridge, England), 140(8), 1730–1739.CrossRefGoogle Scholar
  115. Ramialison, M., et al. (2008). Rapid identification of PAX2/5/8 direct downstream targets in the otic vesicle by combinatorial use of bioinformatics tools. Genome Biology, 9(10), R145.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Represa, J. J., et al. (1990). Patterns of epithelial cell death during early development of the human inner ear. The Annals of Otology, Rhinology, and Laryngology, 99(6 Pt 1), 482–488.PubMedCrossRefGoogle Scholar
  117. Riccomagno, M. M., Takada, S., & Epstein, D. J. (2005). Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes & Development, 19(13), 1612–1623.CrossRefGoogle Scholar
  118. Saburi, S., et al. (2008). Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nature Genetics, 40(8), 1010–1015.PubMedCrossRefGoogle Scholar
  119. Sai, X., & Ladher, R. K. (2008). FGF signaling regulates cytoskeletal remodeling during epithelial morphogenesis. Current Biology: CB, 18(13), 976–981.PubMedCrossRefGoogle Scholar
  120. Sai, X., & Ladher, R. K. (2015). Early steps in inner ear development: Induction and morphogenesis of the otic placode. Frontiers in pharmacology, 6, 19.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Sai, X., Yonemura, S., & Ladher, R. K. (2014). Junctionally restricted RhoA activity is necessary for apical constriction during phase 2 inner ear placode invagination. Developmental Biology, 394(2), 206–216.PubMedCrossRefGoogle Scholar
  122. Sajan, S. A., et al. (2011). Identification of direct downstream targets of Dlx5 during early inner ear development. Human Molecular Genetics, 20(7), 1262–1273.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Salminen, M., et al. (2000). Netrin 1 is required for semicircular canal formation in the mouse inner ear. Development (Cambridge, England), 127(1), 13–22.Google Scholar
  124. Schlosser, G., & Northcutt, R. G. (2000). Development of neurogenic placodes in Xenopus laevis. The Journal of Comparative Neurology, 418(2), 121–146.PubMedCrossRefGoogle Scholar
  125. Shidea, H., et al. (2015). Otic placode cell specification and proliferation are regulated by Notch signaling in avian development. Developmental Dynamics, 244(7), 839–851.CrossRefGoogle Scholar
  126. Sipe, C. W., & Lu, X. (2011). Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms. Development (Cambridge, England), 138(16), 3441–3449.CrossRefGoogle Scholar
  127. Smith, A. N., et al. (2009). Stage-dependent modes of Pax6-Sox2 epistasis regulate lens development and eye morphogenesis. Development (Cambridge, England), 136(17), 2977–2985.CrossRefGoogle Scholar
  128. Streit, A. (2002). Extensive cell movements accompany formation of the otic placode. Developmental Biology, 249(2), 237–254.PubMedCrossRefGoogle Scholar
  129. Strutt, H., & Strutt, D. (2008). Differential stability of flamingo protein complexes underlies the establishment of planar polarity. Current Biology: CB, 18(20), 1555–1564.PubMedPubMedCentralCrossRefGoogle Scholar
  130. Tawk, M., et al. (2007). A mirror-symmetric cell division that orchestrates neuroepithelial morphogenesis. Nature, 446(7137), 797–800.PubMedCrossRefGoogle Scholar
  131. Theveneau, E., et al. (2013). Chase-and-run between adjacent cell populations promotes directional collective migration. Nature Cell Biology, 15(7), 763–772.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Thiede, B. R., et al. (2014). Retinoic acid signalling regulates the development of tonotopically patterned hair cells in the chicken cochlea. Nature communications, 5, 3840.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Torres, M., & Giráldez, F. (1998). The development of the vertebrate inner ear. Mechanisms of Development, 71(1–2), 5–21.PubMedCrossRefGoogle Scholar
  134. Vinson, C. R., & Adler, P. N. (1987). Directional non-cell autonomy and the transmission of polarity information by the frizzled gene of Drosophila. Nature, 329(6139), 549–551.PubMedCrossRefGoogle Scholar
  135. Wallingford, J. B. (2012). Planar cell polarity and the developmental control of cell behavior in vertebrate embryos. Annual Review of Cell and Developmental Biology, 28, 627–653.PubMedCrossRefGoogle Scholar
  136. Wallingford, J. B., et al. (2000). Dishevelled controls cell polarity during Xenopus gastrulation. Nature, 405(6782), 81–85.PubMedCrossRefGoogle Scholar
  137. Wang, Y., Guo, N., & Nathans, J. (2006). The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 26(8), 2147–2156.CrossRefGoogle Scholar
  138. Wang, J., et al. (2005). Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway. Nature Genetics, 37(9), 980–985.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Whitfield, T. T., et al. (2002). Development of the zebrafish inner ear. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 223(4), 427–458.CrossRefGoogle Scholar
  140. Wolf, L. V., et al. (2009). Identification of pax6-dependent gene regulatory networks in the mouse lens. PLoS ONE, 4(1), e4159.PubMedPubMedCentralCrossRefGoogle Scholar
  141. Wong, L. L., & Adler, P. N. (1993). Tissue polarity genes of Drosophila regulate the subcellular location for prehair initiation in pupal wing cells. The Journal of Cell Biology, 123(1), 209–221.PubMedCrossRefGoogle Scholar
  142. Xu, H., Dude, C. M., & Baker, C. V. H. (2008). Fine-grained fate maps for the ophthalmic and maxillomandibular trigeminal placodes in the chick embryo. Developmental Biology, 317(1), 174–186.PubMedCrossRefGoogle Scholar
  143. Yamamoto, N., et al. (2009). Myosin II regulates extension, growth and patterning in the mammalian cochlear duct. Development (Cambridge, England), 136(12), 1977–1986.CrossRefGoogle Scholar
  144. Zheng, L., Zhang, J., & Carthew, R. W. (1995). Frizzled regulates mirror-symmetric pattern formation in the Drosophila eye. Development (Cambridge, England), 121(9), 3045–3055.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Experimental and Health SciencesUniversitat Pompeu Fabra-PRBBBarcelonaSpain
  2. 2.Department of Craniofacial Development and Stem Cell BiologyKing’s College LondonLondonUK

Personalised recommendations