Atoh1 Directs the Formation of Sensory Mosaics and Induces Cell Proliferation in the Postnatal Mammalian Cochlea<i>In Vivo</i>

Kelly, Michael C.; Chang, Qing; Pan, Alex; Lin, Xi; Chen, Ping

doi:10.1523/jneurosci.5420-11.2012

Cited by 200 publications

(294 citation statements)

References 53 publications

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“…13 Consistent with its critical role in coordinating sensory hair cell development and regeneration in the cochlea, 11 here we showed Atoh1 was significantly up-regulated at both mRNA and protein levels in response to Celastrol treatment, which might mechanistically underlie the beneficial effect of Celastrol on inner ear stem cells. Noteworthily, we have not examined thoroughly on the signaling pathways related to Atoh1 activation, since intensive researches have been invested into this subject.…”

Section: Discussionsupporting

confidence: 76%

“…The ectopic introduction of Atoh1 led to formation of supernumerary cochlear sensory hair cells, 1 2 and aberrant overexpression of Atoh1 stimulated trans-differentiation of supporting cells to hair cells. 13 Although investigations into the underlying mechanism have identified Pou4f3, Gfi1 and Myosin 7a as potent downstream effectors, 14 the comprehensive understanding of Atoh1 in the biology of auditory system is still to be fulfilled.…”

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: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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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“…GER cells are immediate neighbors of IBCs, IPhCs, and IHCs and may be less differentiated than SCs in the organ of Corti. GER cells exhibit higher levels of Wnt signaling (e.g., β-catenin and Lgr5) (38)(39)(40)52) and lower levels of Notch signaling (53) and respond readily to Atoh1 (atonal homolog 1) ectopic expression (54)(55)(56)(57). GER cells also express Nestin, a stem/progenitor cell marker in the central nervous system (58).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Lagarde

Wan

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Supporting cells in the cochlea play critical roles in the development, maintenance, and function of sensory hair cells and auditory neurons. Although the loss of hair cells or auditory neurons results in sensorineural hearing loss, the consequence of supporting cell loss on auditory function is largely unknown. In this study, we specifically ablated inner border cells (IBCs) and inner phalangeal cells (IPhCs), the two types of supporting cells surrounding inner hair cells (IHCs) in mice in vivo. We demonstrate that the organ of Corti has the intrinsic capacity to replenish IBCs/IPhCs effectively during early postnatal development. Repopulation depends on the presence of hair cells and cells within the greater epithelial ridge and is independent of cell proliferation. This plastic response in the neonatal cochlea preserves neuronal survival, afferent innervation, and hearing sensitivity in adult mice. In contrast, the capacity for IBC/IPhC regeneration is lost in the mature organ of Corti, and consequently IHC survival and hearing sensitivity are impaired significantly, demonstrating that there is a critical period for the regeneration of cochlear supporting cells. Our findings indicate that the quiescent neonatal organ of Corti can replenish specific supporting cells completely after loss in vivo to guarantee mature hearing function.deafness | cell ablation | hair cell | organ of Corti | glia

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“…However, this ability is confined to early developmental stages, with the competence of the inner ear epithelium to respond to Atoh1 strongly tapering off shortly after birth (19,20). A second temporal aspect is that although Atoh1 is best described for its role in early hair cell specification, temporally controlled knock-out studies have suggested that it is also involved in later aspects of hair cell differentiation and survival (10,21).…”

Section: Context Dependence Of Atoh1mentioning

confidence: 99%

Atoh1 in sensory hair cell development: constraints and cofactors

Costa

Powell

Lowell

et al. 2017

Seminars in Cell & Developmental Biology

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The proneural gene, Atoh1, is necessary and in some contexts sufficient for early inner ear hair cell development. Its function is the subject of intensive research, not least because of the possibility that it could be used in therapeutic strategies to reverse hair cell loss in deafness. However, it is clear that Atoh1's function is highly context dependent. During inner ear development, Atoh1 is only able to promote hair cell differentiation at specific developmental stages. Outside the ear, Atoh1 is required for differentiation of a variety of other cell types, for example in the intestine and cerebellum. The reasons for this context dependence are poorly understood. So far, the pathways and key players that instruct Atoh1 to act as a mechanosensory cell fate determinant in the context of the inner ear are largely unknown. Here we review evidence that suggests that Atoh1 function in hair cell differentiation is modulated by interaction with other transcription factors. We particularly focus on the possible roles of Gfi1 and Pou4f3, drawing from studies in mouse, Drosophila and C. elegans.3

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Atoh1 Directs the Formation of Sensory Mosaics and Induces Cell Proliferation in the Postnatal Mammalian CochleaIn Vivo

Cited by 200 publications

References 53 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

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Atoh1 in sensory hair cell development: constraints and cofactors

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