Full Text:   <2225>

Summary:  <1407>

CLC number: R764.3

On-line Access: 2019-01-22

Received: 2018-02-07

Revision Accepted: 2018-05-23

Crosschecked: 2018-06-06

Cited: 0

Clicked: 5713

Citations:  Bibtex RefMan EndNote GB/T7714


Shan Sun


Hua-Wei Li


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2019 Vol.20 No.2 P.131-145


Bone morphogenetic proteins and inner ear development

Author(s):  Jiao-Yao Ma, Dan You, Wen-Yan Li, Xiao-Ling Lu, Shan Sun, Hua-Wei Li

Affiliation(s):  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 Neurobiology, Fudan University, Shanghai 200031, China; more

Corresponding email(s):   shansun@fudan.edu.cn, lihuawei63@gmail.com

Key Words:  Bone morphogenetic protein (BMP) signaling, Development, Inner ear, Hearing, Balance

Jiao-Yao Ma, Dan You, Wen-Yan Li, Xiao-Ling Lu, Shan Sun, Hua-Wei Li. Bone morphogenetic proteins and inner ear development[J]. Journal of Zhejiang University Science B, 2019, 20(2): 131-145.

@article{title="Bone morphogenetic proteins and inner ear development",
author="Jiao-Yao Ma, Dan You, Wen-Yan Li, Xiao-Ling Lu, Shan Sun, Hua-Wei Li",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Bone morphogenetic proteins and inner ear development
%A Jiao-Yao Ma
%A Dan You
%A Wen-Yan Li
%A Xiao-Ling Lu
%A Shan Sun
%A Hua-Wei Li
%J Journal of Zhejiang University SCIENCE B
%V 20
%N 2
%P 131-145
%@ 1673-1581
%D 2019
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1800084

T1 - Bone morphogenetic proteins and inner ear development
A1 - Jiao-Yao Ma
A1 - Dan You
A1 - Wen-Yan Li
A1 - Xiao-Ling Lu
A1 - Shan Sun
A1 - Hua-Wei Li
J0 - Journal of Zhejiang University Science B
VL - 20
IS - 2
SP - 131
EP - 145
%@ 1673-1581
Y1 - 2019
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1800084

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.



Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[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.

[2]Alsina B, Giraldez F, Pujades C, 2009. Patterning and cell fate in ear development. Int J Dev Biol, 53(8-10):1503-1513.

[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.

[4]Avsian-Kretchmer O, Hsueh AJ, 2004. Comparative genomic analysis of the eight-membered ring cystine knot-containing bone morphogenetic protein antagonists. Mol Endocrinol, 18(1):1-12.

[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.

[6]Barald KF, Kelley MW, 2004. From placode to polarization: new tunes in inner ear development. Development, 131(17):4119-4130.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[15]Chang W, ten Dijke P, Wu DK, 2002. BMP pathways are involved in otic capsule formation and epithelial-mesenchymal signaling in the developing chicken inner ear. Dev Biol, 251(2):380-394.

[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.

[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.

[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.

[19]Das S, Chang C, 2012. Regulation of early Xenopus embryogenesis by Smad ubiquitination regulatory factor 2. Dev Dyn, 241(8):1260-1273.

[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.

[21]Derynck R, Zhang YE, 2003. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature, 425(6958):577-584.

[22]Ekdale EG, 2016. Form and function of the mammalian inner ear. J Anat, 228(2):324-337.

[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.

[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.

[25]Gazzerro E, Canalis E, 2006. Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord, 7(1-2):51-65.

[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.

[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.

[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.

[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.

[30]Groves AK, Bronner-Fraser M, 2000. Competence, specification and commitment in otic placode induction. Development, 127(16):3489-3499.

[31]Hamburger V, Hamilton HL, 1951. A series of normal stages in the development of the chick embryo. J Morphol, 88(1):49-92.

[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.

[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.

[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.

[35]Hoffmann A, Gross G, 2001. BMP signaling pathways in cartilage and bone formation. Crit Rev Eukaryot Gene Expr, 11(1-3):23-45.

[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.

[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.

[38]Ingham PW, McMahon AP, 2001. Hedgehog signaling in animal development: paradigms and principles. Genes Dev, 15(23):3059-3087.

[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.

[40]Izzi L, Attisano L, 2004. Regulation of the TGFβ signalling pathway by ubiquitin-mediated degradation. Oncogene, 23(11):2071-2078.

[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.

[42]Katagiri T, Watabe T, 2016. Bone morphogenetic proteins. Cold Spring Harb Perspect Biol, 8(6):a021899.

[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.

[44]Kelley MW, Wu DK, Popper AN, et al., 2005. Development of the Inner Ear. Springer, New York, NY.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[52]Li Q, 2015. Inhibitory SMADs: potential regulators of ovarian function. Biol Reprod, 92(2):50.

[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.

[54]Liem KF Jr, Tremml G, Roelink H, et al., 1995. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell, 82(6):969-979.

[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.

[56]Liu A, Niswander LA, 2005. Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci, 6(12):945-954.

[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.

[58]Lowery JW, de Caestecker MP, 2010. BMP signaling in vascular development and disease. Cytokine Growth Factor Rev, 21(4):287-298.

[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.

[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.

[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.

[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.

[63]McMahon JA, Takada S, Zimmerman LB, et al., 1998. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev, 12(10):1438-1452.

[64]Mehler MF, Mabie PC, Zhang D, et al., 1997. Bone morphogenetic proteins in the nervous system. Trends Neurosci, 20(7):309-317.

[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.

[66]Miyazawa K, Miyazono K, 2017. Regulation of TGF-β family signaling by inhibitory Smads. Cold Spring Harb Perspect Biol, 9:a022095.

[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.

[68]Miyazono K, Kamiya Y, Morikawa M, 2010. Bone morphogenetic protein receptors and signal transduction. J Biochem, 147(1):35-51.

[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.

[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.

[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.

[72]Mu Y, Gudey SK, Landström M, 2012. Non-Smad signaling pathways. Cell Tissue Res, 347(1):11-20.

[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.

[74]Nakamura J, Yanagita M, 2012. BMP modulators in kidney disease. Discov Med, 13(68):57-63.

[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.

[76]Ohta S, Schoenwolf GC, 2018. Hearing crosstalk: the molecular conversation orchestrating inner ear dorsoventral patterning. WIREs Dev Biol, 7(1):e302.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[84]Pujades C, Kamaid A, Alsina B, et al., 2006. BMP-signaling regulates the generation of hair-cells. Dev Biol, 292(1):55-67.

[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.

[86]Ramel MC, Hill CS, 2012. Spatial regulation of bmp activity. FEBS Lett, 586(14):1929-1941.

[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.

[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.

[89]Rosenzweig BL, Imamura T, Okadome T, et al., 1995. Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA, 92(17):7632-7636.

[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.

[91]Sai X, Ladher RK, 2015. Early steps in inner ear development: induction and morphogenesis of the otic placode. Front Pharmacol, 6:19.

[92]Saint-Jeannet JP, Moody SA, 2014. Establishing the pre-placodal region and breaking it into placodes with distinct identities. Dev Biol, 389(1):13-27.

[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.

[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.

[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.

[96]Urist MR, 1965. Bone: formation by autoinduction. Science, 150(3698):893-899.

[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.

[98]von Bubnoff A, Cho KW, 2001. Intracellular BMP signaling regulation in vertebrates: pathway or network? Dev Biol, 239(1):1-14.

[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.

[100]Whitfield TT, 2015. Development of the inner ear. Curr Opin Genet Dev, 32:112-118.

[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.

[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.

[103]Wordinger RJ, Clark AF, 2007. Bone morphogenetic proteins and their receptors in the eye. Exp Biol Med (Maywood), 232(8):979-992.

[104]Wu DK, Oh SH, 1996. Sensory organ generation in the chick inner ear. J Neurosci, 16(20):6454-6462.

[105]Wu DK, Kelley MW, 2012. Molecular mechanisms of inner ear development. Cold Spring Harb Perspect Biol, 4(8):a008409.

[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.

[107]Zhang YE, 2009. Non-Smad pathways in TGF-β signaling. Cell Res, 19(1):128-139.

[108]Zhang YE, 2017. Non-Smad signaling pathways of the TGF-β family. Cold Spring Harb Perspect Biol, 9(2):a022129.

[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.

[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.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE