Role of Wnt and Notch signaling in regulating hair cell regeneration in the cochlea

Abstract

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

References

[1] Roberson DW, Rubel EW. Cell division in the gerbil cochlea after acoustic trauma. Am J Otol 1994; 15(1): 28–34

[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

[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

[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

[5] Corwin JT, Oberholtzer JC. Fish n’ chicks: model recipes for hair-cell regeneration? Neuron 1997; 19(5): 951–954

[6] Stone JS, Cotanche DA. Hair cell regeneration in the avian auditory epithelium. Int J Dev Biol 2007; 51(6-7): 633–647

[7] Corwin JT, Cotanche DA. Regeneration of sensory hair cells after acoustic trauma. Science 1988; 240(4860): 1772–1774

[8] Ryals BM, Rubel EW. Hair cell regeneration after acoustic trauma in adult Coturnix quail. Science 1988; 240(4860): 1774–1776

[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

[10] Kelley MW. Regulation of cell fate in the sensory epithelia of the inner ear. Nat Rev Neurosci 2006; 7(11): 837–849

[11] Schimmang T. Expression and functions of FGF ligands during early otic development. Int J Dev Biol 2007; 51(6-7): 473–481

[12] Groves AK, Fekete DM. Shaping sound in space: the regulation of inner ear patterning. Development 2012; 139(2): 245–257

[13] Jansson L, Kim GS, Cheng AG. Making sense of Wnt signaling-linking hair cell regeneration to development. Front Cell Neurosci 2015; 9: 66

[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

[16] Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998; 14(1): 59–88

[17] Habas R, Dawid IB. Dishevelled and Wnt signaling: is the nucleus the final frontier? J Biol 2005; 4(1): 2

[18] Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006; 127(3): 469–480

[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

[20] van Amerongen R, Nusse R. Towards an integrated view of Wnt signaling in development. Development 2009; 136(19): 3205–3214

[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

[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

[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

[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

[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

[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

[27] de Lau WB, Snel B, Clevers HC. The R-spondin protein family. Genome Biol 2012; 13(3): 242

[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

[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

[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

[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

[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

[33] Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis 2008; 4(2): 68–75

[34] Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 2006; 281(32): 22429–22433

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[51] Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006; 5(12): 997–1014

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[66] Harper JW. Protein destruction: adapting roles for Cks proteins. Curr Biol 2001; 11(11): R431–R435

[67] Chen P, Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development 1999; 126(8): 1581–1590

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[80] Aster JC. In brief: Notch signalling in health and disease. J Pathol 2014; 232(1): 1–3

[81] Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development 2011; 138(17): 3593–3612

[82] D’Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr Top Dev Biol 2010; 92: 73–129

[83] Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137(2): 216–233

[84] Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006; 7(9): 678–689

[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

[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

[87] Murata J, Ikeda K, Okano H. Notch signaling and the developing inner ear. Adv Exp Med Biol 2012; 727: 161–173

[88] Lewis J. Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 1998; 9(6): 583–589

[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

[90] Chitnis AB. The role of Notch in lateral inhibition and cell fate specification. Mol Cell Neurosci 1995; 6(4): 311–321

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

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