Control of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5

Su, Yixun; Hou, Cong-Cong; Yang, Wan-Xi

doi:10.1016/j.gene.2014.12.054

Cited by 22 publications

(22 citation statements)

References 211 publications

(277 reference statements)

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“…For instance, the Notch signaling has been reported to produce inhibitory bHLH proteins (HES1 and HES5) that blocked the effect of Atoh1 and led to inhibition of the hair cell fate. 9 Upon activation of fibroblast growth factor (FGF) signaling by FGF2, several neurotropic factors such as NGF, BDNF and NT-3 could significantly increase Atoh1 expression, which suggested that FGF signaling played a fundamental role in modulating the specification of progenitor cells and their subsequent differentiation. 9 Accumulating evidences suggest that Wnt/β-catenin signaling is indispensable for pro-sensory cell proliferation as well as sensory hair cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…9 Upon activation of fibroblast growth factor (FGF) signaling by FGF2, several neurotropic factors such as NGF, BDNF and NT-3 could significantly increase Atoh1 expression, which suggested that FGF signaling played a fundamental role in modulating the specification of progenitor cells and their subsequent differentiation. 9 Accumulating evidences suggest that Wnt/β-catenin signaling is indispensable for pro-sensory cell proliferation as well as sensory hair cell differentiation. 22 Through direct interaction with and Atoh1 3′ enhancer, β-catenin stimulated Atoh1 expression in neural progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

“…8 It was reported that the transcription activity of Atoh1 was readily antagonized by the negative regulator of neurogenesis HES1. 9 Loss-of-function of Atoh1 has been identified in the Goblet cell carcinoid and infratentorial cancer. 10 More importantly, Atoh1 is the first gene characterized to be involved in inner ear development, and especially plays a fundamental role in hair cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells

Han

Cong

et al. 2018

Organogenesis

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We aimed to investigate the beneficial effect of Celastrol on inner ear stem cells and potential therapeutic value for hearing loss. The inner ear stem cells were isolated and characterized from utricular sensory epithelium of adult mice. The stemness was evaluated by sphere formation assay. The relative expressions of Atoh1, MAP-2 and Myosin VI were measured by RT-PCR and immunoblotting. The up-regulation of MAP-2 was also analysed with immunofluorescence. The in vitro neuronal excitability was interrogated by calcium oscillation. The electrophysiological property was determined by inward current recorded on patch clamp. Our results demonstrated that Celastrol treatment significantly improved the viability and proliferation of mouse inner ear stem cells, and facilitated sphere formation. Moreover, Celastrol stimulated differentiation of mouse inner ear stem cells to neuronal-like cells and enhanced neural excitability. Celastrol also enhanced neuronal-like cell identity in the inner ear stem cell derived neurons, as well as their electrophysiological function. Most notably, these effects were apparently associated with the upregulation of Atoh1 in response to Celastrol treatment. Celastrol showed beneficial effect on inner ear stem cells and held therapeutic promise against hearing loss.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells

Han

Cong

et al. 2018

Organogenesis

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“…Mutations in Alms1 cause Alstrom's syndrome, which is an autosomal recessive syndromic genetic disorder with sensorineural hearing loss (Bermingham-McDonogh et al, 2001; White et al, 2012). Lif controls neural differentiation and maintenance of stem cell-derived murine spiral ganglion neuron precursors (Marzella et al, 1999; Su et al, 2015). Hes1, Hes5, Hey1 , and HeyL are downstream effectors of the Notch pathway and have been reported to negatively regulate HC differentiation and regeneration (Zheng et al, 2000; Zine et al, 2001; Li et al, 2008; Murata et al, 2009; Abdolazimi et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Lgr5+ Progenitor Cell Transcriptomes after Neomycin Injury in the Neonatal Mouse Cochlea

Zhang

Yu³

et al. 2017

Front. Mol. Neurosci.

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Lgr5+ supporting cells (SCs) are enriched hair cell (HC) progenitors in the cochlea. Both in vitro and in vivo studies have shown that HC injury can spontaneously activate Lgr5+ progenitors to regenerate HCs in the neonatal mouse cochlea. Promoting HC regeneration requires the understanding of the mechanism of HC regeneration, and this requires knowledge of the key genes involved in HC injury-induced self-repair responses that promote the proliferation and differentiation of Lgr5+ progenitors. Here, as expected, we found that neomycin-treated Lgr5+ progenitors (NLPs) had significantly greater HC regeneration ability, and greater but not significant proliferation ability compared to untreated Lgr5+ progenitors (ULPs) in response to neomycin exposure. Next, we used RNA-seq analysis to determine the differences in the gene-expression profiles between the transcriptomes of NLPs and ULPs from the neonatal mouse cochlea. We first analyzed the genes that were enriched and differentially expressed in NLPs and ULPs and then analyzed the cell cycle genes, the transcription factors, and the signaling pathway genes that might regulate the proliferation and differentiation of Lgr5+ progenitors. We found 9 cell cycle genes, 88 transcription factors, 8 microRNAs, and 16 cell-signaling pathway genes that were significantly upregulated or downregulated after neomycin injury in NLPs. Lastly, we constructed a protein-protein interaction network to show the interaction and connections of genes that are differentially expressed in NLPs and ULPs. This study has identified the genes that might regulate the proliferation and HC regeneration of Lgr5+ progenitors after neomycin injury, and investigations into the roles and mechanisms of these genes in the cochlea should be performed in the future to identify potential therapeutic targets for HC regeneration.

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“…Many of the genes responsible for the remarkable structure and the unique functions of this highly specialized cell have now been identified e.g. [1,2]. In contrast, despite progress in identifying transcription factors (TFs) critical for inner ear development individually, there has been less progress in understanding how target genes are specifically regulated in HCs.…”

Section: Introductionmentioning

confidence: 99%

The Promoter and Multiple Enhancers of the pou4f3 Gene Regulate Expression in Inner Ear Hair Cells

Masuda

Pak

et al. 2016

Mol Neurobiol

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Few enhancers that target gene expression to inner ear hair cells (HCs) have been identified. Using transgenic analysis of eGFP reporter constructs and bioinformatics, we evaluated the control of pou4f3 gene expression, since it is expressed only in HCs within the inner ear, and continues to be expressed throughout life. An 8.5 kb genomic DNA fragment 5’ to the start codon, containing three regions of high cross-species homology drove expression in all embryonic and neonatal HCs, and adult vestibular and inner HCs, but not adult outer HCs. Transgenes with 0.4, 0.8, 2.5 or 6.5 kb of 5’ DNA did not produce HC expression. However, addition of the region from 6.5 to 7.2 kb produced expression in vestibular HCs and neonatal basal turn outer HCs, which also implicated the region from 7.2 kb to 8.5 kb in inner and apical outer HC expression. Deletion of the region from 0.4 to 5.5 kb 5’ from the 8.5 kb construct did not affect HC expression, further indicating lack of HC regulatory elements. When the region from 1 to 0.4 kb was replaced with the minimal promoter of the Ela1 gene, HC expression was maintained, but at a drastically reduced level. Bioinformatics identified regions of highly conserved sequence outside of the 8.5 kb, which contained POU4F3, GFI1, and LHX3 binding sites. These regions may be involved in maintaining POU4F3 expression in adult outer HCs. Our results identify separate enhancers at various locations that direct expression to different HC types at different ages, and determine that 0.4 kb of upstream sequence determines expression level. These data will assist in the identification of mutations in noncoding, regulatory regions of this deafness gene.

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Control of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5

Cited by 22 publications

References 211 publications

Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells

Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells

Characterization of Lgr5+ Progenitor Cell Transcriptomes after Neomycin Injury in the Neonatal Mouse Cochlea

The Promoter and Multiple Enhancers of the pou4f3 Gene Regulate Expression in Inner Ear Hair Cells

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