Journal of Zhejiang University-SCIENCE B

, Volume 20, Issue 2, pp 131–145 | Cite as

Bone morphogenetic proteins and inner ear development

  • Jiao-yao Ma
  • Dan You
  • Wen-yan Li
  • Xiao-ling Lu
  • Shan SunEmail author
  • Hua-wei LiEmail author


Bone morphogenetic proteins (BMPs) are the largest subfamily of the transforming growth factor-β superfamily, and they play important roles in the development of numerous organs, including the inner ear. The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance. Here, we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.

Key words

Bone morphogenetic protein (BMP) signaling Development Inner ear Hearing Balance 



骨形态发生蛋白(BMP)是转化生长因子-β 超家族中最大的亚家族, 它们在许多器官(包括内耳) 的发育中发挥重要作用。 内耳是一个较小的器官, 但其具有非常复杂的结构并且与听觉和平衡相关。 本文先着重于 BMPs 及其 BMP 信号通路的介绍, 后以内耳的发育时间为轴线, 配合图片, 介绍了 BMP 信号通路在内耳发育的不同阶段的影响以及对于内耳的不同部位的发育的影响, 并概括了最新的内耳发育领域关于 BMP 信号通路的研究, 为之后的内耳发育以及毛细胞再生的研究提供参考。


骨形态发生蛋白(BMP)信号通路 发育 内耳 听觉 平衡 

CLC number



  1. Abelló G, Khatri S, Radosevic M, et al., 2010. Independent regulation of Sox3 and Lmx1b by FGF and BMP signaling influences the neurogenic and non–neurogenic domains in the chick otic placode. Dev Biol, 339(1): 166–178. Google Scholar
  2. Alsina B, Giraldez F, Pujades C, 2009. Patterning and cell fate in ear development. Int J Dev Biol, 53(8–10): 1503–1513. Google Scholar
  3. Alvarez IS, Navascués J, 1990. Shaping, invagination, and closure of the chick embryo otic vesicle: scanning electron microscopic and quantitative study. Anat Rec, 228(3): 315–326. Google Scholar
  4. Avsian-Kretchmer O, Hsueh AJ, 2004. Comparative genomic analysis of the eight–membered ring cystine knotcontaining bone morphogenetic protein antagonists. Mol Endocrinol, 18(1): 1–12. Google Scholar
  5. Bai S, Cao X, 2002. A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor–β signaling. J Biol Chem, 277(6): 4176–4182. Google Scholar
  6. Barald KF, Kelley MW, 2004. From placode to polarization: new tunes in inner ear development. Development, 131(17): 4119–4130. Google Scholar
  7. Blauwkamp MN, Beyer LA, Kabara L, et al., 2007. The role of bone morphogenetic protein 4 in inner ear development and function. Hear Res, 225(1–2): 71–79. Google Scholar
  8. Bok J, Brunet LJ, Howard O, et al., 2007. Role of hindbrain in inner ear morphogenesis: analysis of Noggin knockout mice. Dev Biol, 311(1): 69–78. Google Scholar
  9. Bond AM, Bhalala OG, Kessler JA, 2012. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev Neurobiol, 72(7): 1068–1084. Google Scholar
  10. Brazil DP, Church RH, Surae S, et al., 2015. BMP signalling: agony and antagony in the family. Trends Cell Biol, 25(5): 249–264. Google Scholar
  11. Brunet LJ, McMahon JA, McMahon AP,et al., 1998. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science, 280(5368): 1455–1457. Google Scholar
  12. Carreira AC, Lojudice FH, Halcsik E, et al., 2014a. Bone morphogenetic proteins: facts, challenges, and future perspectives. J Dent Res, 93(4): 335–345. Google Scholar
  13. Carreira AC, Alves GG, Zambuzzi WF,et al., 2014b. Bone morphogenetic proteins: structure, biological function and therapeutic applications. Arch Biochem Biophys, 561(6): 64–73. Google Scholar
  14. Chang W, Nunes FD, de Jesus–Escobar JM,et al., 1999. Ectopic noggin blocks sensory and nonsensory organ morphogenesis in the chicken inner ear. Dev Biol, 216(1): 369–381. Google Scholar
  15. Chang W, ten Dijke P, Wu DK, 2002. BMP pathways are involved in otic capsule formation and epithelialmesenchymal signaling in the developing chicken inner ear. Dev Biol, 251(2): 380–394. Google Scholar
  16. Chang W, Lin Z, Kulessa H, et al., 2008. Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements. PLoS Genet, 4(4): e1000050. Google Scholar
  17. Chen G, Deng C, Li YP, 2012. TGF–β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci, 8(2): 272–288. Google Scholar
  18. Cole LK, le Roux I, Nunes F, et al., 2000. Sensory organ generation in the chicken inner ear: contributions of Bone morphogenetic protein 4, Serrate1, and Lunatic fringe. J Comp Neurol, 424(3): 509–520. 3<509:: AID–CNE8>3.0.CO;2–Q<Google Scholar
  19. Das S, Chang C, 2012. Regulation of early Xenopus embryogenesis by Smad ubiquitination regulatory factor 2. Dev Dyn, 241(8): 1260–1273. Google Scholar
  20. David D, Nair SA, Pillai MR, 2013. Smurf E3 ubiquitin ligases at the cross roads of oncogenesis and tumor suppression. Biochim Biophys Acta, 1835(1): 119–128. Google Scholar
  21. Derynck R, Zhang YE, 2003. Smad–dependent and Smadindependent pathways in TGF–β family signalling. Nature, 425(6958): 577–584. Google Scholar
  22. Ekdale EG, 2016. Form and function of the mammalian inner ear. J Anat, 228(2): 324–337. Google Scholar
  23. Fritzsch B, Beisel KW, Hansen LA, 2006. The molecular basis of neurosensory cell formation in ear development: a blueprint for hair cell and sensory neuron regeneration? Bioessays, 28(12): 1181–1193. Google Scholar
  24. Garside VC, Chang AC, Karsan A, et al., 2013. Co–ordinating Notch, BMP, and TGF–β signaling during heart valve development. Cell Mol Life Sci, 70(16): 2899–2917. Google Scholar
  25. Gazzerro E, Canalis E, 2006. Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord, 7(1–2): 51–65. Google Scholar
  26. Gerlach LM, Hutson MR, Germiller JA,et al., 2000. Addition of the BMP4 antagonist, noggin, disrupts avian inner ear development. Development, 127(1): 45–54.Google Scholar
  27. Gerlach–Bank LM, Ellis AD, Noonen B, et al., 2002. Cloning and expression analysis of the chick DAN gene, an antagonist of the BMP family of growth factors. Dev Dyn, 224(1): 109–115. Google Scholar
  28. Gerlach–Bank LM, Cleveland AR, Barald KF, 2004. DAN directs endolymphatic sac and duct outgrowth in the avian inner ear. Dev Dyn, 229(2): 219–230. Google Scholar
  29. Glavic A, Maris Honoré S, Gloria Feijóo C, et al., 2004. Role of BMP signaling and the homeoprotein iroquois in the specification of the cranial placodal field. Dev Biol, 272(1): 89–103. Google Scholar
  30. Groves AK, Bronner–Fraser M, 2000. Competence, specification and commitment in otic placode induction. Development, 127(16): 3489–3499.Google Scholar
  31. Hamburger V, Hamilton HL, 1951. A series of normal stages in the development of the chick embryo. J Morphol, 88(1): 49–92.Google Scholar
  32. Hata A, Lagna G, Massagué J, et al., 1998. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev, 12(2): 186–197.Google Scholar
  33. Heldin CH, Miyazono K, ten Dijke P, 1997. TGF–β signalling from cell membrane to nucleus through SMAD proteins. Nature, 390(6659): 465–471. Google Scholar
  34. Hemmati–Brivanlou A, Thomsen GH, 1995. Ventral mesodermal patterning in Xenopus embryos: expression patterns and activities of BMP–2 and BMP–4. Dev Genet, 17(1): 78–89. Google Scholar
  35. Hoffmann A, Gross G, 2001. BMP signaling pathways in cartilage and bone formation. Crit Rev Eukaryot Gene Expr, 11(1–3): 23–45.Google Scholar
  36. Huang J, Liu Y, Filas B, et al., 2015. Negative and positive auto–regulation of BMP expression in early eye development. Dev Biol, 407(2): 256–264. Google Scholar
  37. Hwang CH, Guo D, Harris MA,et al., 2010. Role of bone morphogenetic proteins on cochlear hair cell formation: analyses of Noggin and Bmp2 mutant mice. Dev Dyn, 239(2): 505–513. Google Scholar
  38. Ingham PW, McMahon AP, 2001. Hedgehog signaling in animal development: paradigms and principles. Genes Dev, 15(23): 3059–3087. Google Scholar
  39. Ishimura A, Maeda R, Takeda M, et al., 2000. Involvement of BMP–4/msx–1 and FGF pathways in neural induction in the Xenopus embryo. Dev Growth Differ, 42(4): 307–316. Google Scholar
  40. Izzi L, Attisano L, 2004. Regulation of the TGFβ signalling pathway by ubiquitin–mediated degradation. Oncogene, 23(11): 2071–2078. Google Scholar
  41. Jones CM, Lyons KM, Hogan BL, 1991. Involvement of bone morphogenetic protein–4 (BMP–4) and Vgr–1 in morphogenesis and neurogenesis in the mouse. Development, 111(2): 531–542.Google Scholar
  42. Katagiri T, Watabe T, 2016. Bone morphogenetic proteins. Cold Spring Harb Perspect Biol, 8(6): a021899. Google Scholar
  43. Kattamuri C, Luedeke DM, Nolan K, et al., 2012. Members of the DAN family are BMP antagonists that form highly stable noncovalent dimers. J Mol Biol, 424(5): 313–327. Google Scholar
  44. Kelley MW, Wu DK, Popper AN,et al., 2005. Development of the Inner Ear. Springer, New York, NY. Google Scholar
  45. Kessler E, Takahara K, Biniaminov L, et al., 1996. Bone morphogenetic protein–1: the type I procollagen C–proteinase. Science, 271(5247): 360–362. Google Scholar
  46. Kil SH, Collazo A, 2001. Origins of inner ear sensory organs revealed by fate map and time–lapse analyses. Dev Biol, 233(2): 365–379. Google Scholar
  47. Krispin S, Nitzan E, Kalcheim C, 2010. The dorsal neural tube: a dynamic setting for cell fate decisions. Dev Neurobiol, 70(12): 796–812. Google Scholar
  48. Kwon HJ, Bhat N, Sweet EM,et al., 2010. Identification of early requirements for preplacodal ectoderm and sensory organ development. PLoS Genet, 6(9): e1001133. Google Scholar
  49. Lee KJ, Jessell TM, 1999. The specification of dorsal cell fates in the vertebrate central nervous system. Annu Rev Neurosci, 22(1): 261–294. Google Scholar
  50. Lee KJ, Mendelsohn M, Jessell TM, 1998. Neuronal patterning by BMPs: a requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord. Genes Dev, 12(21): 3394–3407. Google Scholar
  51. Li H, Corrales CE, Wang Z, et al., 2005. BMP4 signaling is involved in the generation of inner ear sensory epithelia. BMC Dev Biol, 5: 16. Google Scholar
  52. Li Q, 2015. Inhibitory SMADs: potential regulators of ovarian function. Biol Reprod, 92(2): 50. Google Scholar
  53. Li W, Cogswell CA, Loturco JJ, 1998. Neuronal differentiation of precursors in the neocortical ventricular zone is triggered by BMP. J Neurosci, 18(21): 8853–8862. Google Scholar
  54. Liem KFJr, Tremml G, Roelink H, et al., 1995. Dorsal differentiation of neural plate cells induced by BMPmediated signals from epidermal ectoderm. Cell, 82(6): 969–979. Google Scholar
  55. Litsiou A, Hanson S, Streit A, 2005. A balance of FGF, BMP and WNT signalling positions the future placode territory in the head. Development, 132(18): 4051–4062. Google Scholar
  56. Liu A, Niswander LA, 2005. Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci, 6(12): 945–954. Google Scholar
  57. Liu W, Oh SH, Kang YK,et al., 2003. Bone morphogenetic protein 4 (BMP4): a regulator of capsule chondrogenesis in the developing mouse inner ear. Dev Dyn, 226(3): 427–438. Google Scholar
  58. Lowery JW, de Caestecker MP, 2010. BMP signaling in vascular development and disease. Cytokine Growth Factor Rev, 21(4): 287–298. Google Scholar
  59. Mabie PC, Mehler MF, Kessler JA, 1999. Multiple roles of bone morphogenetic protein signaling in the regulation of cortical cell number and phenotype. J Neurosci, 19(16): 7077–7088. Google Scholar
  60. Macias MJ, Martin–Malpartida P, Massagué J, 2015. Structural determinants of Smad function in TGF–β signaling. Trends Biochem Sci, 40(6): 296–308. Google Scholar
  61. Mann ZF, Thiede BR, Chang W, et al., 2014. A gradient of Bmp7 specifies the tonotopic axis in the developing inner ear. Nat Commun, 5: 3839. Google Scholar
  62. Martin P, Swanson GJ, 1993. Descriptive and experimental analysis of the epithelial remodellings that control semicircular canal formation in the developing mouse inner ear. Dev Biol, 159(2): 549–558. Google Scholar
  63. McMahon JA, Takada S, Zimmerman LB,et al., 1998. Nogginmediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev, 12(10): 1438–1452. Google Scholar
  64. Mehler MF, Mabie PC, Zhang D, et al., 1997. Bone morphogenetic proteins in the nervous system. Trends Neurosci, 20(7): 309–317. Google Scholar
  65. Mehler MF, Mabie PC, Zhu G, et al., 2000. Developmental changes in progenitor cell responsiveness to bone morphogenetic proteins differentially modulate progressive CNS lineage fate. Dev Neurosci, 22(1–2): 74–85. Google Scholar
  66. Miyazawa K, Miyazono K, 2017. Regulation of TGF–β family signaling by inhibitory Smads. Cold Spring Harb Perspect Biol, 9: a022095. Google Scholar
  67. Miyazono K, Maeda S, Imamura T, 2005. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross–talk. Cytokine Growth Factor Rev, 16(3): 251–263. Google Scholar
  68. Miyazono K, Kamiya Y, Morikawa M, 2010. Bone morphogenetic protein receptors and signal transduction. J Biochem, 147(1): 35–51. Google Scholar
  69. Moon BS, Yoon JY, Kim MY,et al., 2009. Bone morphogenetic protein 4 stimulates neuronal differentiation of neuronal stem cells through the ERK pathway. Exp Mol Med, 41(2): 116–125. Google Scholar
  70. Morsli H, Choo D, Ryan A, et al., 1998. Development of the mouse inner ear and origin of its sensory organs. J Neurosci, 18(9): 3327–3335. Google Scholar
  71. Mowbray C, Hammerschmidt M, Whitfield TT, 2001. Expression of BMP signalling pathway members in the developing zebrafish inner ear and lateral line. Mech Dev, 108(1–2): 179–184. Google Scholar
  72. Mu Y, Gudey SK, Landström M, 2012. Non–Smad signaling pathways. Cell Tissue Res, 347(1): 11–20. Google Scholar
  73. Munnamalai V, Fekete DM, 2016. Notch–Wnt–Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner. Development, 143(21): 4003–4015. Google Scholar
  74. Nakamura J, Yanagita M, 2012. BMP modulators in kidney disease. Discov Med, 13(68): 57–63.Google Scholar
  75. Oh SH, Johnson R, Wu DK, 1996. Differential expression of bone morphogenetic proteins in the developing vestibular and auditory sensory organs. J Neurosci, 16(20): 6463–6475. Google Scholar
  76. Ohta S, Schoenwolf GC, 2018. Hearing crosstalk: the molecular conversation orchestrating inner ear dorsoventral patterning. WIREs Dev Biol, 7(1): e302. Google Scholar
  77. Ohta S, Wang B, Mansour SL,et al., 2016a. BMP regulates regional gene expression in the dorsal otocyst through canonical and non–canonical intracellular pathways. Development, 143(12): 2228–2237. Google Scholar
  78. Ohta S, Wang B, Mansour SL,et al., 2016b. SHH ventralizes the otocyst by maintaining basal PKA activity and regulating GLI3 signaling. Dev Biol, 420(1): 100–109. Google Scholar
  79. Ohyama T, Groves AK, Martin K, 2007. The first steps towards hearing: mechanisms of otic placode induction. Int J Dev Biol, 51(6–7): 463–472. Google Scholar
  80. Ohyama T, Basch ML, Mishina Y, et al., 2010. BMP signaling is necessary for patterning the sensory and nonsensory regions of the developing mammalian cochlea. J Neurosci, 30(45): 15044–15051. Google Scholar
  81. Omata Y, Nojima Y, Nakayama S, et al., 2007. Role of bone morphogenetic protein 4 in zebrafish semicircular canal development. Dev Growth Differ, 49(9): 711–719. Google Scholar
  82. Pandit T, Jidigam VK, Patthey C, et al., 2015. Neural retina identity is specified by lens–derived BMP signals. Development, 142(10): 1850–1859. Google Scholar
  83. Piccolo S, Sasai Y, Lu B, et al., 1996. Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP–4. Cell, 86(4): 589–598. Google Scholar
  84. Pujades C, Kamaid A, Alsina B, et al., 2006. BMP–signaling regulates the generation of hair–cells. Dev Biol, 292(1): 55–67. Google Scholar
  85. Puligilla C, Feng F, Ishikawa K, et al., 2007. Disruption of fibroblast growth factor receptor 3 signaling results in defects in cellular differentiation, neuronal patterning, and hearing impairment. Dev Dyn, 236(7): 1905–1917. Google Scholar
  86. Ramel MC, Hill CS, 2012. Spatial regulation of bmp activity. FEBS Lett, 586(14): 1929–1941. Google Scholar
  87. Reichert S, Randall RA, Hill CS, 2013. A BMP regulatory network controls ectodermal cell fate decisions at the neural plate border. Development, 140(21): 4435–4444. Google Scholar
  88. Riccomagno MM, Martinu L, Mulheisen M, et al., 2002. Specification of the mammalian cochlea is dependent on Sonic hedgehog. Genes Dev, 16(18): 2365–2378. Google Scholar
  89. Rosenzweig BL, Imamura T, Okadome T, et al., 1995. Cloning and characterization of a human type IIreceptor for bone morphogenetic proteins. Proc Natl Acad Sci USA, 92(17): 7632–7636. Google Scholar
  90. Ruiz i Altaba A, Jessell TM, 1991. Retinoic acid modifies the pattern of cell differentiation in the central nervous system of neurula stage Xenopus embryos. Development, 112(4): 945–958.Google Scholar
  91. Sai X, Ladher RK, 2015. Early steps in inner ear development: induction and morphogenesis of the otic placode. Front Pharmacol, 6: 19. Google Scholar
  92. Saint-Jeannet JP, Moody SA, 2014. Establishing the preplacodal region and breaking it into placodes with distinct identities. Dev Biol, 389(1): 13–27. Google Scholar
  93. Shi Y, Wang YF, Jayaraman L, et al., 1998. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-β signaling. Cell, 94(5): 585–594. Google Scholar
  94. Sieber C, Kopf J, Hiepen C, et al., 2009. Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev, 20(5–6): 343–355. Google Scholar
  95. Takemura T, Sakagami M, Takebayashi K, et al., 1996. Localization of bone morphogenetic protein-4 messenger RNA in developing mouse cochlea. Hear Res, 95(1–2): 26–32. Google Scholar
  96. Urist MR, 1965. Bone: formation by autoinduction. Science, 150(3698): 893–899.Google Scholar
  97. Vervoort R, Ceulemans H, van Aerschot L, et al., 2010. Genetic modification of the inner ear lateral semicircular canal phenotype of the BMP4 haplo-insufficient mouse. Biochem Biophys Res Commun, 394(3): 780–785. Google Scholar
  98. von Bubnoff A, Cho KW, 2001. Intracellular BMP signaling regulation in vertebrates: pathway or network? Dev Biol, 239(1): 1–14. Google Scholar
  99. Waqas M, Sun S, Xuan C, et al., 2017. Bone morphogenetic protein 4 promotes the survival and preserves the structure of flow-sorted Bhlhb5+ cochlear spiral ganglion neurons in vitro. Sci Rep, 7(1): 3506. Google Scholar
  100. Whitfield TT, 2015. Development of the inner ear. Curr Opin Genet Dev, 32: 112–118. Google Scholar
  101. Wijgerde M, Karp S, McMahon J, et al., 2005. Noggin antagonism of BMP4 signaling controls development of the axial skeleton in the mouse. Dev Biol, 286(1): 149–157. Google Scholar
  102. Winnier G, Blessing M, Labosky PA,et al., 1995. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev, 9(17): 2105–2116. Google Scholar
  103. Wordinger RJ, Clark AF, 2007. Bone morphogenetic proteins and their receptors in the eye. Exp Biol Med (Maywood), 232(8): 979–992. Google Scholar
  104. Wu DK, Oh SH, 1996. Sensory organ generation in the chick inner ear. J Neurosci, 16(20): 6454–6462. Google Scholar
  105. Wu DK, Kelley MW, 2012. Molecular mechanisms of inner ear development. Cold Spring Harb Perspect Biol, 4(8): a008409. Google Scholar
  106. Zhang J, Zhang X, Xie F, et al., 2014. The regulation of TGF-β/SMAD signaling by protein deubiquitination. Protein Cell, 5(7): 503–517. Google Scholar
  107. Zhang YE, 2009. Non-Smad pathways in TGF-β signaling. Cell Res, 19(1): 128–139. Google Scholar
  108. Zhang YE, 2017. Non–Smad signaling pathways of the TGF-β family. Cold Spring Harb Perspect Biol, 9(2): a022129. Google Scholar
  109. Zhu H, Kavsak P, Abdollah S, et al., 1999. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature, 400(6745): 687–693. Google Scholar
  110. Zimmerman LB, de Jesús–Escobar JM, Harland RM, 1996. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell, 86(4): 599–606. Google Scholar

Copyright information

© Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Ear, Nose & Throat Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, NHC Key Laboratory of Hearing Medicine, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina
  2. 2.Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain ScienceFudan UniversityShanghaiChina

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