Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (3) : 237-249     DOI: 10.1007/s11684-016-0464-9
Role of Wnt and Notch signaling in regulating hair cell regeneration in the cochlea
Muhammad Waqas,Shasha Zhang,Zuhong He,Mingliang Tang(),Renjie Chai()
Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
Download: PDF(400 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Sensory hair cells in the inner ear are responsible for sound recognition. Damage to hair cells in adult mammals causes permanent hearing impairment because these cells cannot regenerate. By contrast, newborn mammals possess limited regenerative capacity because of the active participation of various signaling pathways, including Wnt and Notch signaling. The Wnt and Notch pathways are highly sophisticated and conserved signaling pathways that control multiple cellular events necessary for the formation of sensory hair cells. Both signaling pathways allow resident supporting cells to regenerate hair cells in the neonatal cochlea. In this regard, Wnt and Notch signaling has gained increased research attention in hair cell regeneration. This review presents the current understanding of the Wnt and Notch signaling pathways in the auditory portion of the inner ear and discusses the possibilities of controlling these pathways with the hair cell fate determiner Atoh1 to regulate hair cell regeneration in the mammalian cochlea.

Keywords inner ear      cochlea      hair cell      regeneration      Wnt      Notch      signaling pathways     
Corresponding Authors: Mingliang Tang,Renjie Chai   
Just Accepted Date: 19 July 2016   Online First Date: 12 August 2016    Issue Date: 30 August 2016
URL:     OR
Fig.1  Schematic of the cochlear sensory epithelium in mammals. OHC, outer hair cell; IHC, inner hair cell; SCs, supporting cells; TOC, tunnel of Corti; TM, tectorial membrane; NFs, nerve fibers; HB, hair bundle.
Fig.2  Schematic of the canonical Wnt/b and non-canonical PCP pathways. For canonical Wnt, signaling begins with the Frizzled and LRP receptor complex, which stimulates and stabilizes b-catenin via the Disheveled (Dsh) and other proteins, including adenomatosis polyposis coli (APC), axin, and glycogen synthase kinase 3 (GSK3b). b-Catenin accumulates in the cytoplasm, then translocates into the nucleus to form complexes with the TCF/LEF family of transcription factors to regulate the expression of downstream Wnt target genes. For the non-canonical PCP pathway, Wnt signaling is initiated through Frizzled without any involvement of the LRP receptor. By utilizing the activation of Dsh, this pathway regulates cytoskeletal restructuring by activating small GTPases Rho and Rac.
Fig.3  Schematic of the Notch signaling pathway. Notch ligands and receptors are both found in the cell membranes of two neighboring cells. The binding of Notch ligands with the receptors stimulates the proteolytic cleavage of the Notch receptor either by the ADAM family of metalloproteases or by g-secretase. The cleavage liberates the Notch intracellular domain (NICD) from the transmembrane receptor, and the NICD then translocates into the nucleus to form a complex with the CSL DNA binding protein and the transcriptional co-activator Mastermind-like protein (MAML). This three-protein transcriptional complex regulates the expression of Notch target genes such as Hes5, Hey1, Myc, and P21. The transcription of HES repressors halts the expression of cell-growth-specific transcriptional activators such as members of basic helix–loop–helix transcription factors (Atoh1). In the “off” mode of Notch signaling, the three-protein complex is not formed and the cell-growth-specific transcription activators promote cell proliferation and differentiation.
Fig.4  Model of the integrative role of canonical Wnt and Notch signaling in HC regeneration. The schematic representation depicts how the deliberate inhibition of Notch signaling promotes the differentiation of SCs into HCs, at the same time promoting the accumulation of b-catenin. Activation of canonical Wnt signaling turns on the genetic machinery necessary to promote the proliferation of SCs and to mitotically regenerate HCs.
1 Roberson DW, Rubel EW. Cell division in the gerbil cochlea after acoustic trauma. Am J Otol 1994; 15(1): 28–34
pmid: 8109626
2 Cox BC, Chai R, Lenoir A, Liu Z, Zhang L, Nguyen DH, Chalasani K, Steigelman KA, Fang J, Rubel EW, Cheng AG, Zuo J. Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development 2014; 141(4): 816–829
doi: 10.1242/dev.103036 pmid: 24496619
3 Bramhall NF, Shi F, Arnold K, Hochedlinger K, Edge AS. Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea. Stem Cell Rep 2014; 2(3): 311–322
doi: 10.1016/j.stemcr.2014.01.008 pmid: 24672754
4 Cruz RM, Lambert PR, Rubel EW. Light microscopic evidence of hair cell regeneration after gentamicin toxicity in chick cochlea. Arch Otolaryngol Head Neck Surg 1987; 113(10): 1058–1062
doi: 10.1001/archotol.1987.01860100036017 pmid: 3620125
5 Corwin JT, Oberholtzer JC. Fish n’ chicks: model recipes for hair-cell regeneration? Neuron 1997; 19(5): 951–954
doi: 10.1016/S0896-6273(00)80386-4 pmid: 9390508
6 Stone JS, Cotanche DA. Hair cell regeneration in the avian auditory epithelium. Int J Dev Biol 2007; 51(6-7): 633–647
doi: 10.1387/ijdb.072408js pmid: 17891722
7 Corwin JT, Cotanche DA. Regeneration of sensory hair cells after acoustic trauma. Science 1988; 240(4860): 1772–1774
doi: 10.1126/science.3381100 pmid: 3381100
8 Ryals BM, Rubel EW. Hair cell regeneration after acoustic trauma in adult Coturnix quail. Science 1988; 240(4860): 1774–1776
doi: 10.1126/science.3381101 pmid: 3381101
9 Cotanche DA, Saunders JC, Tilney LG. Hair cell damage produced by acoustic trauma in the chick cochlea. Hear Res 1987; 25(2-3): 267–286
doi: 10.1016/0378-5955(87)90098-0 pmid: 3558135
10 Kelley MW. Regulation of cell fate in the sensory epithelia of the inner ear. Nat Rev Neurosci 2006; 7(11): 837–849
doi: 10.1038/nrn1987 pmid: 17053809
11 Schimmang T. Expression and functions of FGF ligands during early otic development. Int J Dev Biol 2007; 51(6-7): 473–481
doi: 10.1387/ijdb.072334ts pmid: 17891710
12 Groves AK, Fekete DM. Shaping sound in space: the regulation of inner ear patterning. Development 2012; 139(2): 245–257
doi: 10.1242/dev.067074 pmid: 22186725
13 Jansson L, Kim GS, Cheng AG. Making sense of Wnt signaling-linking hair cell regeneration to development. Front Cell Neurosci 2015; 9: 66
doi: 10.3389/fncel.2015.00066 pmid: 25814927
14 Zak M, Klis SF, Grolman W. The Wnt and Notch signalling pathways in the developing cochlea: formation of hair cells and induction of regenerative potential. Int J Dev Neurosci 2015; 47(Pt B):247–258
15 Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20(1): 781–810
doi: 10.1146/annurev.cellbio.20.010403.113126 pmid: 15473860
16 Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998; 14(1): 59–88
doi: 10.1146/annurev.cellbio.14.1.59 pmid: 9891778
17 Habas R, Dawid IB. Dishevelled and Wnt signaling: is the nucleus the final frontier? J Biol 2005; 4(1): 2
doi: 10.1186/jbiol22 pmid: 15720723
18 Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006; 127(3): 469–480
doi: 10.1016/j.cell.2006.10.018 pmid: 17081971
19 Jin T, George Fantus I, Sun J. Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of β-catenin. Cell Signal 2008; 20(10): 1697–1704
doi: 10.1016/j.cellsig.2008.04.014 pmid: 18555664
20 van Amerongen R, Nusse R. Towards an integrated view of Wnt signaling in development. Development 2009; 136(19): 3205–3214
doi: 10.1242/dev.033910 pmid: 19736321
21 Jacques BE, Puligilla C, Weichert RM, Ferrer-Vaquer A, Hadjantonakis AK, Kelley MW, Dabdoub A. A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea. Development 2012; 139(23): 4395–4404
doi: 10.1242/dev.080358 pmid: 23132246
22 Shi F, Hu L, Jacques BE, Mulvaney JF, Dabdoub A, Edge AS. b-Catenin is required for hair-cell differentiation in the cochlea. J Neurosci 2014; 34(19): 6470–6479
doi: 10.1523/JNEUROSCI.4305-13.2014 pmid: 24806673
23 Stevens CB, Davies AL, Battista S, Lewis JH, Fekete DM. Forced activation of Wnt signaling alters morphogenesis and sensory organ identity in the chicken inner ear. Dev Biol 2003; 261(1): 149–164
doi: 10.1016/S0012-1606(03)00297-5 pmid: 12941626
24 Jin YR, Yoon JK. The R-spondin family of proteins: emerging regulators of WNT signaling. Int J Biochem Cell Biol 2012; 44(12): 2278–2287
doi: 10.1016/j.biocel.2012.09.006 pmid: 22982762
25 Mulvaney JF, Yatteau A, Sun WW, Jacques B, Takubo K, Suda T, Yamada W, Dabdoub A. Secreted factor R-Spondin 2 is involved in refinement of patterning of the mammalian cochlea. Dev Dyn 2013; 242(2): 179–188
doi: 10.1002/dvdy.23908 pmid: 23192966
26 de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es JE, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 2011; 476(7360): 293–297
doi: 10.1038/nature10337 pmid: 21727895
27 de Lau WB, Snel B, Clevers HC. The R-spondin protein family. Genome Biol 2012; 13(3): 242
doi: 10.1186/gb-2012-13-3-242 pmid: 22439850
28 Chai R, Xia A, Wang T, Jan TA, Hayashi T, Bermingham-McDonogh O, Cheng AG. Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. J Assoc Res Otolaryngol 2011; 12(4): 455–469
doi: 10.1007/s10162-011-0267-2 pmid: 21472479
29 Zhang Y, Chen Y, Ni W, Guo L, Lu X, Liu L, Li W, Sun S, Wang L, Li H. Dynamic expression of Lgr6 in the developing and mature mouse cochlea. Front Cell Neurosci 2015; 9: 165
doi: 10.3389/fncel.2015.00165 pmid: 26029045
30 Chai R, Kuo B, Wang T, Liaw EJ, Xia A, Jan TA, Liu Z, Taketo MM, Oghalai JS, Nusse R, Zuo J, Cheng AG. Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea. Proc Natl Acad Sci USA 2012; 109(21): 8167–8172
doi: 10.1073/pnas.1202774109 pmid: 22562792
31 He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way. Development 2004; 131(8): 1663–1677
doi: 10.1242/dev.01117 pmid: 15084453
32 Wallingford JB, Habas R. The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 2005; 132(20): 4421–4436
doi: 10.1242/dev.02068 pmid: 16192308
33 Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis 2008; 4(2): 68–75
doi: 10.4161/org.4.2.5851 pmid: 19279717
34 Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 2006; 281(32): 22429–22433
doi: 10.1074/jbc.R600015200 pmid: 16793760
35 Dabdoub A, Kelley MW. Planar cell polarity and a potential role for a Wnt morphogen gradient in stereociliary bundle orientation in the mammalian inner ear. J Neurobiol 2005; 64(4): 446–457
doi: 10.1002/neu.20171 pmid: 16041762
36 Dabdoub A, Donohue MJ, Brennan A, Wolf V, Montcouquiol M, Sassoon DA, Hseih JC, Rubin JS, Salinas PC, Kelley MW. Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea. Development 2003; 130(11): 2375–2384
doi: 10.1242/dev.00448 pmid: 12702652
37 Lewis J, Davies A. Planar cell polarity in the inner ear: how do hair cells acquire their oriented structure? J Neurobiol 2002; 53(2): 190–201
doi: 10.1002/neu.10124 pmid: 12382275
38 Qian D, Jones C, Rzadzinska A, Mark S, Zhang X, Steel KP, Dai X, Chen P. Wnt5a functions in planar cell polarity regulation in mice. Dev Biol 2007; 306(1): 121–133
doi: 10.1016/j.ydbio.2007.03.011 pmid: 17433286
39 Wang Y, Guo N, Nathans J. The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. J Neurosci 2006; 26(8): 2147–2156
doi: 10.1523/JNEUROSCI.4698-05.2005 pmid: 16495441
40 Montcouquiol M, Rachel RA, Lanford PJ, Copeland NG, Jenkins NA, Kelley MW. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 2003; 423(6936): 173–177
doi: 10.1038/nature01618 pmid: 12724779
41 Ren DD, Kelly M, Kim SM, Grimsley-Myers CM, Chi FL, Chen P. Testin interacts with vangl2 genetically to regulate inner ear sensory cell orientation and the normal development of the female reproductive tract in mice. Dev Dyn 2013; 242(12): 1454–1465
doi: 10.1002/dvdy.24042 pmid: 23996638
42 Lu X, Borchers AG, Jolicoeur C, Rayburn H, Baker JC, Tessier-Lavigne M. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature 2004; 430(6995): 93–98
doi: 10.1038/nature02677 pmid: 15229603
43 Jones C, Qian D, Kim SM, Li S, Ren D, Knapp L, Sprinzak D, Avraham KB, Matsuzaki F, Chi F, Chen P. Ankrd6 is a mammalian functional homolog of Drosophila planar cell polarity gene diego and regulates coordinated cellular orientation in the mouse inner ear. Dev Biol 2014; 395(1): 62–72
doi: 10.1016/j.ydbio.2014.08.029 pmid: 25218921
44 Sipe CW, Lu X. Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms. Development 2011; 138(16): 3441–3449
doi: 10.1242/dev.065961 pmid: 21752934
45 Kirjavainen A, Laos M, Anttonen T, Pirvola U. The Rho GTPase Cdc42 regulates hair cell planar polarity and cellular patterning in the developing cochlea. Biol Open 2015; 4(4): 516–526
doi: 10.1242/bio.20149753 pmid: 25770185
46 Andre P, Wang Q, Wang N, Gao B, Schilit A, Halford MM, Stacker SA, Zhang X, Yang Y. The Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2. J Biol Chem 2012; 287(53): 44518–44525
doi: 10.1074/jbc.M112.414441 pmid: 23144463
47 Romero-Carvajal A, Navajas Acedo J, Jiang L, Kozlovskaja-Gumbrienė A, Alexander R, Li H, Piotrowski T. Regeneration of sensory hair cells requires localized interactions between the Notch and Wnt pathways. Dev Cell 2015; 34(3): 267–282
doi: 10.1016/j.devcel.2015.05.025 pmid: 26190147
48 Head JR, Gacioch L, Pennisi M, Meyers JR. Activation of canonical Wnt/β-catenin signaling stimulates proliferation in neuromasts in the zebrafish posterior lateral line. Dev Dyn 2013; 242(7): 832–846
doi: 10.1002/dvdy.23973 pmid: 23606225
49 Jacques BE, Montgomery WH 4th, Uribe PM, Yatteau A, Asuncion JD, Resendiz G, Matsui JI, Dabdoub A. The role of Wnt/β-catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line. Dev Neurobiol 2014; 74(4): 438–456
doi: 10.1002/dneu.22134 pmid: 24115534
50 Jiang L, Romero-Carvajal A, Haug JS, Seidel CW, Piotrowski T. Gene-expression analysis of hair cell regeneration in the zebrafish lateral line. Proc Natl Acad Sci USA 2014; 111(14): E1383–E1392
doi: 10.1073/pnas.1402898111 pmid: 24706903
51 Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006; 5(12): 997–1014
doi: 10.1038/nrd2154 pmid: 17139285
52 Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgård R. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet 2008; 40(11): 1291–1299
doi: 10.1038/ng.239 pmid: 18849992
53 Shi F, Kempfle JS, Edge AS. Wnt-responsive Lgr5-expressing stem cells are hair cell progenitors in the cochlea. J Neurosci 2012; 32(28): 9639–9648
doi: 10.1523/JNEUROSCI.1064-12.2012 pmid: 22787049
54 Wang T, Chai R, Kim GS, Pham N, Jansson L, Nguyen DH, Kuo B, May LA, Zuo J, Cunningham LL, Cheng AG. Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nat Commun 2015; 6: 6613
doi: 10.1038/ncomms7613 pmid: 25849379
55 Shi F, Hu L, Edge AS. Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors. Proc Natl Acad Sci USA 2013; 110(34): 13851–13856
doi: 10.1073/pnas.1219952110 pmid: 23918377
56 Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F. Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 2002; 22(4): 1172–1183
doi: 10.1128/MCB.22.4.1172-1183.2002 pmid: 11809808
57 Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 2002; 22(4): 1184–1193
doi: 10.1128/MCB.22.4.1184-1193.2002 pmid: 11809809
58 Jan TA, Chai R, Sayyid ZN, van Amerongen R, Xia A, Wang T, Sinkkonen ST, Zeng YA, Levin JR, Heller S, Nusse R, Cheng AG. Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells. Development 2013; 140(6): 1196–1206
doi: 10.1242/dev.087528 pmid: 23444352
59 Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, Bellen HJ, Lysakowski A, Zoghbi HY. Math1: an essential gene for the generation of inner ear hair cells. Science 1999; 284(5421): 1837–1841
doi: 10.1126/science.284.5421.1837 pmid: 10364557
60 Chen P, Johnson JE, Zoghbi HY, Segil N. The role of Math1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 2002; 129(10): 2495–2505
pmid: 11973280
61 Shi F, Cheng YF, Wang XL, Edge AS. β-catenin up-regulates Atoh1 expression in neural progenitor cells by interaction with an Atoh1 3′ enhancer. J Biol Chem 2010; 285(1): 392–400
doi: 10.1074/jbc.M109.059055 pmid: 19864427
62 Kuo BR, Baldwin EM, Layman WS, Taketo MM, Zuo J. In vivo cochlear hair cell generation and survival by coactivation of β-catenin and Atoh1. J Neurosci 2015; 35(30): 10786–10798
doi: 10.1523/JNEUROSCI.0967-15.2015 pmid: 26224861
63 Lu X, Sun S, Qi J, Li W, Liu L, Zhang Y, Chen Y, Zhang S, Wang L, Miao D, Chai R, Li H. Bmi1 regulates the proliferation of cochlear supporting cells via the canonical Wnt signaling pathway. Mol Neurobiol 2016 Feb 3. [Epub ahead of print] doi: 10.1007/s12035-016-9686-8
pmid: 26843109
64 Liu L, Chen Y, Qi J, Zhang Y, He Y, Ni W, Li W, Zhang S, Sun S, Taketo MM, Wang L, Chai R, Li H. Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea. Cell Death Dis 2016; 7(3): e2136
doi: 10.1038/cddis.2016.35 pmid: 26962686
65 Murata J, Ohtsuka T, Tokunaga A, Nishiike S, Inohara H, Okano H, Kageyama R. Notch-Hes1 pathway contributes to the cochlear prosensory formation potentially through the transcriptional down-regulation of p27Kip1. J Neurosci Res 2009; 87(16): 3521–3534
doi: 10.1002/jnr.22169 pmid: 19598246
66 Harper JW. Protein destruction: adapting roles for Cks proteins. Curr Biol 2001; 11(11): R431–R435
doi: 10.1016/S0960-9822(01)00253-6 pmid: 11516665
67 Chen P, Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development 1999; 126(8): 1581–1590
pmid: 10079221
68 Löwenheim H, Furness DN, Kil J, Zinn C, Göltig K, Fero ML, Frost D, Gummer AW, Roberts JM, Rubel EW, Hackney CM, Zenner HP. Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. Proc Natl Acad Sci USA 1999; 96(7): 4084–4088
doi: 10.1073/pnas.96.7.4084 pmid: 10097167
69 Doetzlhofer A, White P, Lee YS, Groves A, Segil N. Prospective identification and purification of hair cell and supporting cell progenitors from the embryonic cochlea. Brain Res 2006; 1091(1): 282–288
doi: 10.1016/j.brainres.2006.02.071 pmid: 16616734
70 White PM, Doetzlhofer A, Lee YS, Groves AK, Segil N. Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 2006; 441(7096): 984–987
doi: 10.1038/nature04849 pmid: 16791196
71 Ono K, Nakagawa T, Kojima K, Matsumoto M, Kawauchi T, Hoshino M, Ito J. Silencing p27 reverses post-mitotic state of supporting cells in neonatal mouse cochleae. Mol Cell Neurosci 2009; 42(4): 391–398
doi: 10.1016/j.mcn.2009.08.011 pmid: 19733668
72 Nakayama KI, Hatakeyama S, Nakayama K. Regulation of the cell cycle at the G1-S transition by proteolysis of cyclin E and p27Kip1. Biochem Biophys Res Commun 2001; 282(4): 853–860
doi: 10.1006/bbrc.2001.4627 pmid: 11352628
73 Minoda R, Izumikawa M, Kawamoto K, Zhang H, Raphael Y. Manipulating cell cycle regulation in the mature cochlea. Hear Res 2007; 232(1-2): 44–51
doi: 10.1016/j.heares.2007.06.005 pmid: 17658230
74 Oesterle EC, Chien WM, Campbell S, Nellimarla P, Fero ML. p27(Kip1) is required to maintain proliferative quiescence in the adult cochlea and pituitary. Cell Cycle 2011; 10(8): 1237–1248
doi: 10.4161/cc.10.8.15301 pmid: 21403466
75 Walters BJ, Liu Z, Crabtree M, Coak E, Cox BC, Zuo J. Auditory hair cell-specific deletion of p27Kip1 in postnatal mice promotes cell-autonomous generation of new hair cells and normal hearing. J Neurosci 2014; 34(47): 15751–15763
doi: 10.1523/JNEUROSCI.3200-14.2014 pmid: 25411503
76 Laine H, Doetzlhofer A, Mantela J, Ylikoski J, Laiho M, Roussel MF, Segil N, Pirvola U. p19(Ink4d) and p21(Cip1) collaborate to maintain the postmitotic state of auditory hair cells, their codeletion leading to DNA damage and p53-mediated apoptosis. J Neurosci 2007; 27(6): 1434–1444
doi: 10.1523/JNEUROSCI.4956-06.2007 pmid: 17287518
77 Ji P, Zhu L. Using kinetic studies to uncover new Rb functions in inhibiting cell cycle progression. Cell Cycle 2005; 4(3): 373–375
doi: 10.4161/cc.4.3.1535 pmid: 15701969
78 Sage C, Huang M, Karimi K, Gutierrez G, Vollrath MA, Zhang DS, García-Añoveros J, Hinds PW, Corwin JT, Corey DP, Chen ZY. Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science 2005; 307(5712): 1114–1118
doi: 10.1126/science.1106642 pmid: 15653467
79 Rocha-Sanchez SM, Scheetz LR, Contreras M, Weston MD, Korte M, McGee J, Walsh EJ. Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells. J Neurosci 2011; 31(24): 8883–8893
doi: 10.1523/JNEUROSCI.5821-10.2011 pmid: 21677172
80 Aster JC. In brief: Notch signalling in health and disease. J Pathol 2014; 232(1): 1–3
doi: 10.1002/path.4291 pmid: 24122372
81 Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development 2011; 138(17): 3593–3612
doi: 10.1242/dev.063610 pmid: 21828089
82 D’Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr Top Dev Biol 2010; 92: 73–129
doi: 10.1016/S0070-2153(10)92003-6 pmid: 20816393
83 Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137(2): 216–233
doi: 10.1016/j.cell.2009.03.045 pmid: 19379690
84 Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006; 7(9): 678–689
doi: 10.1038/nrm2009 pmid: 16921404
85 Neves J, Abelló G, Petrovic J, Giraldez F. Patterning and cell fate in the inner ear: a case for Notch in the chicken embryo. Dev Growth Differ 2013; 55(1): 96–112
doi: 10.1111/dgd.12016 pmid: 23252974
86 Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003; 194(3): 237–255
doi: 10.1002/jcp.10208 pmid: 12548545
87 Murata J, Ikeda K, Okano H. Notch signaling and the developing inner ear. Adv Exp Med Biol 2012; 727: 161–173
doi: 10.1007/978-1-4614-0899-4_12 pmid: 22399346
88 Lewis J. Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 1998; 9(6): 583–589
doi: 10.1006/scdb.1998.0266 pmid: 9892564
89 Daudet N, Lewis J. Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation. Development 2005; 132(3): 541–551
doi: 10.1242/dev.01589 pmid: 15634704
90 Chitnis AB. The role of Notch in lateral inhibition and cell fate specification. Mol Cell Neurosci 1995; 6(4): 311–321
doi: 10.1006/mcne.1995.1024 pmid: 8742272
91 Bryant J, Goodyear RJ, Richardson GP. Sensory organ development in the inner ear: molecular and cellular mechanisms. Br Med Bull 2002; 63(1): 39–57
doi: 10.1093/bmb/63.1.39 pmid: 12324383
92 Brooker R, Hozumi K, Lewis J. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 2006; 133(7): 1277–1286
doi: 10.1242/dev.02284 pmid: 16495313
93 Kiernan AE, Xu J, Gridley T. The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet 2006; 2(1): e4
doi: 10.1371/journal.pgen.0020004 pmid: 16410827
94 Munnamalai V, Hayashi T, Bermingham-McDonogh O. Notch prosensory effects in the mammalian cochlea are partially mediated by Fgf20. J Neurosci 2012; 32(37): 12876–12884
doi: 10.1523/JNEUROSCI.2250-12.2012 pmid: 22973011
95 Hartman BH, Reh TA, Bermingham-McDonogh O. Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear. Proc Natl Acad Sci USA 2010; 107(36): 15792–15797
doi: 10.1073/pnas.1002827107 pmid: 20798046
96 Liu Z, Owen T, Fang J, Zuo J. Overactivation of Notch1 signaling induces ectopic hair cells in the mouse inner ear in an age-dependent manner. PLoS ONE 2012; 7(3): e34123
doi: 10.1371/journal.pone.0034123 pmid: 22448289
97 Pan W, Jin Y, Chen J, Rottier RJ, Steel KP, Kiernan AE. Ectopic expression of activated notch or SOX2 reveals similar and unique roles in the development of the sensory cell progenitors in the mammalian inner ear. J Neurosci 2013; 33(41): 16146–16157
doi: 10.1523/JNEUROSCI.3150-12.2013 pmid: 24107947
98 Daudet N, Ariza-McNaughton L, Lewis J. Notch signalling is needed to maintain, but not to initiate, the formation of prosensory patches in the chick inner ear. Development 2007; 134(12): 2369–2378
doi: 10.1242/dev.001842 pmid: 17537801
99 Zine A, Aubert A, Qiu J, Therianos S, Guillemot F, Kageyama R, de Ribaupierre F. Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. J Neurosci 2001; 21(13): 4712–4720
pmid: 11425898
100 Kiernan AE, Cordes R, Kopan R, Gossler A, Gridley T. The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development 2005; 132(19): 4353–4362
doi: 10.1242/dev.02002 pmid: 16141228
101 Lanford PJ, Lan Y, Jiang R, Lindsell C, Weinmaster G, Gridley T, Kelley MW. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 1999; 21(3): 289–292
doi: 10.1038/6804 pmid: 10080181
102 Petrovic J, Gálvez H, Neves J, Abelló G, Giraldez F. Differential regulation of Hes/Hey genes during inner ear development. Dev Neurobiol 2015; 75(7): 703–720
doi: 10.1002/dneu.22243 pmid: 25363712
103 Ma EY, Rubel EW, Raible DW. Notch signaling regulates the extent of hair cell regeneration in the zebrafish lateral line. J Neurosci 2008; 28(9): 2261–2273
doi: 10.1523/JNEUROSCI.4372-07.2008 pmid: 18305259
104 Daudet N, Gibson R, Shang J, Bernard A, Lewis J, Stone J. Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds. Dev Biol 2009; 326(1): 86–100
doi: 10.1016/j.ydbio.2008.10.033 pmid: 19013445
105 Takebayashi S, Yamamoto N, Yabe D, Fukuda H, Kojima K, Ito J, Honjo T. Multiple roles of Notch signaling in cochlear development. Dev Biol 2007; 307(1): 165–178
doi: 10.1016/j.ydbio.2007.04.035 pmid: 17531970
106 Batts SA, Shoemaker CR, Raphael Y. Notch signaling and Hes labeling in the normal and drug-damaged organ of Corti. Hear Res 2009; 249(1-2): 15–22
doi: 10.1016/j.heares.2008.12.008 pmid: 19185606
107 Korrapati S, Roux I, Glowatzki E, Doetzlhofer A. Notch signaling limits supporting cell plasticity in the hair cell-damaged early postnatal murine cochlea. PLoS ONE 2013; 8(8): e73276
doi: 10.1371/journal.pone.0073276 pmid: 24023676
108 Mizutari K, Fujioka M, Hosoya M, Bramhall N, Okano HJ, Okano H, Edge AS. Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 2013; 77(1): 58–69
doi: 10.1016/j.neuron.2012.10.032 pmid: 23312516
109 Hartman BH, Basak O, Nelson BR, Taylor V, Bermingham-McDonogh O, Reh TA. Hes5 expression in the postnatal and adult mouse inner ear and the drug-damaged cochlea. J Assoc Res Otolaryngol 2009; 10(3): 321–340
doi: 10.1007/s10162-009-0162-2 pmid: 19373512
110 Oesterle EC, Campbell S, Taylor RR, Forge A, Hume CR. Sox2 and JAGGED1 expression in normal and drug-damaged adult mouse inner ear. J Assoc Res Otolaryngol 2008; 9(1): 65–89
doi: 10.1007/s10162-007-0106-7 pmid: 18157569
111 Tona Y, Hamaguchi K, Ishikawa M, Miyoshi T, Yamamoto N, Yamahara K, Ito J, Nakagawa T. Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing loss. BMC Neurosci 2014; 15(1): 66
doi: 10.1186/1471-2202-15-66 pmid: 24884926
112 Maass JC, Gu R, Basch ML, Waldhaus J, Lopez EM, Xia A, Oghalai JS, Heller S, Groves AK. Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea. Front Cell Neurosci 2015; 9: 110
doi: 10.3389/fncel.2015.00110 pmid: 25873862
113 Yamamoto N, Tanigaki K, Tsuji M, Yabe D, Ito J, Honjo T. Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas. J Mol Med (Berl) 2006; 84(1): 37–45
doi: 10.1007/s00109-005-0706-9 pmid: 16283144
114 Doetzlhofer A, Basch ML, Ohyama T, Gessler M, Groves AK, Segil N. Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell 2009; 16(1): 58–69
doi: 10.1016/j.devcel.2008.11.008 pmid: 19154718
115 Li W, Wu J, Yang J, Sun S, Chai R, Chen ZY, Li H. Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc Natl Acad Sci USA 2015; 112(1): 166–171
doi: 10.1073/pnas.1415901112 pmid: 25535395
116 Morrison A, Hodgetts C, Gossler A, Hrabé de Angelis M, Lewis J. Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear. Mech Dev 1999; 84(1-2): 169–172
doi: 10.1016/S0925-4773(99)00066-0 pmid: 10473135
117 Jayasena CS, Ohyama T, Segil N, Groves AK. Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. Development 2008; 135(13): 2251–2261
doi: 10.1242/dev.017905 pmid: 18495817
118 Agathocleous M, Iordanova I, Willardsen MI, Xue XY, Vetter ML, Harris WA, Moore KB. A directional Wnt/β-catenin-Sox2-proneural pathway regulates the transition from proliferation to differentiation in the Xenopus retina. Development 2009; 136(19): 3289–3299
doi: 10.1242/dev.040451 pmid: 19736324
119 Katoh M, Katoh M. Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med 2006; 17(4): 681–685
pmid: 16525728
120 Woods C, Montcouquiol M, Kelley MW. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat Neurosci 2004; 7(12): 1310–1318
doi: 10.1038/nn1349 pmid: 15543141
[1] Yan Chen,Wenyan Li,Wen Li,Renjie Chai,Huawei Li. Spatiotemporal expression of Ezh2 in the developing mouse cochlear sensory epithelium[J]. Front. Med., 2016, 10(3): 330-335.
[2] Yanfei Wang,Yueyue Liu,Hongyun Nie,Xin Ma,Zhigang Xu. Alternative splicing of inner-ear-expressed genes[J]. Front. Med., 2016, 10(3): 250-257.
[3] Aining Xu,Lin Cheng. Chemical transdifferentiation: closer to regenerative medicine[J]. Front. Med., 2016, 10(2): 152-165.
[4] Wenyan Li,Dan You,Yan Chen,Renjie Chai,Huawei Li. Regeneration of hair cells in the mammalian vestibular system[J]. Front. Med., 2016, 10(2): 143-151.
[5] Samuel Chege Gitau,Xuelian Li,Dandan Zhao,Zhenfeng Guo,Haihai Liang,Ming Qian,Lifang Lv,Tianshi Li,Bozhi Xu,Zhiguo Wang,Yong Zhang,Chaoqian Xu,Yanjie Lu,Zhiming Du,Hongli Shan,Baofeng Yang. Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling[J]. Front. Med., 2015, 9(4): 444-456.
[6] Siming Yang, Sha Huang, Changjiang Feng, Xiaobing Fu. Umbilical cord-derived mesenchymal stem cells: strategies, challenges, and potential for cutaneous regeneration[J]. Front Med, 2012, 6(1): 41-47.
[7] Zhiyuan Zhang. Bone regeneration by stem cell and tissue engineering in oral and maxillofacial region[J]. Front Med, 2011, 5(4): 401-413.
[8] ZHANG Xufeng, YU Liang, LU Yi. Wnt/β-catenin signaling pathway and its role in hepatocellular carcinoma[J]. Front. Med., 2008, 2(3): 216-228.
[9] GE Jian, LIU Jingbo. The stem cell and tissue engineering research in Chinese ophthalmology[J]. Front. Med., 2007, 1(1): 6-10.
Full text