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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    https://doi.org/10.1007/s11684-016-0464-9
REVIEW
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
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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     
Corresponding Author(s): Mingliang Tang,Renjie Chai   
Just Accepted Date: 19 July 2016   Online First Date: 12 August 2016    Issue Date: 30 August 2016
 Cite this article:   
Muhammad Waqas,Shasha Zhang,Zuhong He, et al. Role of Wnt and Notch signaling in regulating hair cell regeneration in the cochlea[J]. Front. Med., 2016, 10(3): 237-249.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-016-0464-9
https://academic.hep.com.cn/fmd/EN/Y2016/V10/I3/237
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.
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