title: Co-regulation of the Notch and Wnt signaling pathways promotes supporting cell proliferation and hair cell regeneration in mouse utricles.
abstract: This work sought to determine the crosstalk between the Notch and Wnt signaling pathways in regulating supporting cell (SC) proliferation and hair cell (HC) regeneration in mouse utricles. We cultured postnatal day (P)3 and P60 mouse utricles, damaged the HCs with gentamicin, and treated the utricles with the γ-secretase inhibitor DAPT to inhibit the Notch pathway and with the Wnt agonist QS11 to active the Wnt pathway. We also used Sox2-CreER, Notch1-flox (exon 1), and Catnb-flox (exon 3) transgenic mice to knock out the Notch pathway and activate the Wnt pathway in Sox2+ SCs. Notch inhibition alone increased SC proliferation and HC number in both undamaged and damaged utricles. Wnt activation alone promoted SC proliferation, but the HC number was not significantly increased. Here we demonstrated the cumulative effects of Notch inhibition and Wnt activation in regulating SC proliferation and HC regeneration. Simultaneously inhibiting Notch and overexpressing Wnt led to significantly greater SC proliferation and greater numbers of HCs than manipulating either pathway alone. Similar results were observed in the transgenic mice. This study suggests that the combination of Notch inhibition and Wnt activation can significantly promote SC proliferation and increase the number of regenerated HCs in mouse utricle.
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China.
authors.forename: Jingfang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Lin
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, PR China.|Central laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, 200031, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, 200031, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, PR China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, PR China.|Central laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, 200031, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, 200031, PR China.
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.affiliation: MOE Key Laboratory of Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, PR China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, PR China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Tang
authors.affiliation: MOE Key Laboratory of Developmental Genes and Human Disease, State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, PR China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, PR China.
authors.forename: Renjie
authors.initials: R
authors.lastname: Chai
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, 200031, PR China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002478:Cells, Cultured / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation; D005839:Gentamicins / Q000737:chemistry; D006198:Hair Cells, Auditory / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000378:metabolism*; D012038:Regeneration; D012444:Saccule and Utricle / Q000254:growth & development / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D005839:Gentamicins; D051880:Receptors, Notch; D051153:Wnt Proteins; D051176:beta Catenin