Inhibitors of Differentiation and DNA Binding (Ids) Regulate Math1 and Hair Cell Formation during the Development of the Organ of Corti

Jones, Jennifer M.; Montcouquiol, Mireille; Dabdoub, Alain; Woods, Chad; Kelley, Matthew W.

doi:10.1523/jneurosci.3859-05.2006

Cited by 126 publications

(138 citation statements)

References 55 publications

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“…All the auditory and vestibular hair cells were absent in Atoh1 deficient mice, 2 4 and ectopic re-introduction of wild-type Atoh1 restored the hair cell fate within both the pro-sensory domain and non-sensory regions of the cochlea. 25 In line with these observations, our data demonstrated that Celastrol enhanced neuronal-like cell identity in the inner ear stem cell population as well as their electrophysiological function, which was highly likely to be mediated by the up-regulation of Atoh1. In addition to preservation and stimulation of the regeneration capacity, here we provided evidences that Celastrol treatment also enhanced the differentiation of inner ear stem cells into neuronal-like cells, and their electrophysiological functioning.…”

Section: Discussionsupporting

confidence: 86%

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: 86%

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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“…4A). Inhibitors of differentiation and DNA binding (Ids) 1, 2, and 3 all negatively regulate Atoh1 by competitive-binding to E proteins (Connerney et al 2006;Jones et al 2006) (Fig. 4B).…”

Section: Post-translational Regulationmentioning

confidence: 99%

Atoh1, an Essential Transcription Factor in Neurogenesis and Intestinal and Inner Ear Development: Function, Regulation, and Context Dependency

Mulvaney

Dabdoub

2012

JARO

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Atoh1 (also known as Math1, Hath1, and Cath1 in mouse, human, and chicken, respectively) is a proneural basic helix-loop-helix (bHLH) transcription factor that is required in a variety of developmental contexts. Atoh1 is involved in differentiation of neurons, secretory cells in the gut, and mechanoreceptors including auditory hair cells. Together with the two closely related bHLH genes, Neurog1 and NeuroD1, Atoh1 regulates neurosensory development in the ear as well as neurogenesis in the cerebellum. Atoh1 activity in the cochlea is both necessary and sufficient to drive auditory hair cell differentiation, in keeping with its known role as a regulator of various genes that are markers of terminal differentiation. Atoh1 is known in other fields as an oncogene and a tumor suppressor involved in regulation of cell cycle control and apoptosis. Aberrant Atoh1 activity in adult tissue is implicated in cancer progression, specifically in medullablastoma and adenomatous polyposis carcinoma. We demonstrate through protein sequence comparison that Atoh1 contains conserved phosphorylation sites outside the bHLH domain, which may allow regulation through post-translational modification. With such diverse roles, tight regulation of Atoh1 at both the transcriptional and protein level is essential.

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“…Western blot analyses carried out by the manufacturer on murine samples have demonstrated that this antibody, as well as the anti-Jagged1 (C-20) antibody discussed below, does not cross-react and recognizes a single protein of the correct size (150 kDa molecular weight). Others have used the H-114 antibody in mouse inner ear (Zine and de Ribaupierre 2002;Woods et al 2004;Kiernan et al 2006;Jones et al 2006). Jagged1 is an affinity purified goat polyclonal antibody raised against the C-terminus of human Jagged1.…”

Section: Antibodiesmentioning

confidence: 99%

“…Jagged1 is expressed in embryonic SCs in mouse organ of Corti, but its expression in the adult ear is unknown (Zine and de Ribaupierre 2002;Woods et al 2004;Brooker et al 2006;Jones et al 2006;Murata et al 2006). Because of its presence in developing SCs, we examined its expression in normal and drugdamaged adult ears.…”

Section: Normalsmentioning

confidence: 99%

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Oesterle

Campbell

Taylor³

et al. 2007

JARO

218

245

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Inner ear hair cells detect environmental signals associated with hearing, balance, and body orientation. In humans and other mammals, significant hair cell loss leads to irreversible hearing and balance deficits, whereas hair cell loss in nonmammalian vertebrates is repaired by the spontaneous generation of replacement hair cells. Research in mammalian hair cell regeneration is hampered by the lack of in vivo damage models for the adult mouse inner ear and the paucity of cell-type-specific markers for nonsensory cells within the sensory receptor epithelia. The present study delineates a protocol to drug damage the adult mouse auditory epithelium (organ of Corti) in situ and uses this protocol to investigate Sox2 and Jagged1 expression in damaged inner ear sensory epithelia. In other tissues, the transcription factor Sox2 and a ligand member of the Notch signaling pathway, Jagged1, are involved in regenerative processes. Both are involved in early inner ear development and are expressed in developing support cells, but little is known about their expressions in the adult. We describe a nonsurgical technique for inducing hair cell damage in adult mouse organ of Corti by a single high-dose injection of the aminoglycoside kanamycin followed by a single injection of the loop diuretic furosemide. This drug combination causes the rapid death of outer hair cells throughout the cochlea. Using immunocytochemical techniques, Sox2 is shown to be expressed specifically in support cells in normal adult mouse inner ear and is not affected by drug damage. Sox2 is absent from auditory hair cells, but is expressed in a subset of vestibular hair cells. Double-labeling experiments with Sox2 and calbindin suggest Sox2-positive hair cells are Type II. Jagged1 is also expressed in support cells in the adult ear and is not affected by drug damage. Sox2 and Jagged1 may be involved in the maintenance of support cells in adult mouse inner ear.

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Inhibitors of Differentiation and DNA Binding (Ids) Regulate Math1 and Hair Cell Formation during the Development of the Organ of Corti

Abstract: The basic helix-loop-helix (bHLH) transcription factor Math1 (also calledAtoh1

Cited by 126 publications

References 55 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

Atoh1, an Essential Transcription Factor in Neurogenesis and Intestinal and Inner Ear Development: Function, Regulation, and Context Dependency

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

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