Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea

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dc.contributor.authorMaass, Juan
dc.contributor.authorGu, Rende
dc.contributor.authorBasch, Martin
dc.contributor.authorWaldhaus, Joerg
dc.contributor.authorLopez, Eduardo
dc.contributor.authorXia, Anping
dc.contributor.authorOghalai, John
dc.contributor.authorHeller, Stefan
dc.contributor.authorGroves, Andrew
dc.date.accessioned2017-05-05T16:12:36Z
dc.date.available2017-05-05T16:12:36Z
dc.date.issued2015
dc.description.abstractSensorineural hearing loss is most commonly caused by the death of hair cells in the organ of Corti, and once lost, mammalian hair cells do not regenerate. In contrast, other vertebrates such as birds can regenerate hair cells by stimulating division and differentiation of neighboring supporting cells. We currently know little of the genetic networks which become active in supporting cells when hair cells die and that are activated in experimental models of hair cell regeneration. Several studies have shown that neonatal mammalian cochlear supporting cells are able to trans-differentiate into hair cells when cultured in conditions in which the Notch signaling pathway is blocked. We now show that the ability of cochlear supporting cells to trans-differentiate declines precipitously after birth, such that supporting cells from six-day-old mouse cochlea are entirely unresponsive to a blockade of the Notch pathway. We show that this trend is seen regardless of whether the Notch pathway is blocked with gamma secretase inhibitors, or by antibodies against the Notch1 receptor, suggesting that the action of gamma secretase inhibitors on neonatal supporting cells is likely to be by inhibiting Notch receptor cleavage. The loss of responsiveness to inhibition of the Notch pathway in the first postnatal week is due in part to a down-regulation of Notch receptors and ligands, and we show that this down-regulation persists in the adult animal, even under conditions of noise damage. Our data suggest that the Notch pathway is used to establish the repeating pattern of hair cells and supporting cells in the organ of Corti, but is not required to maintain this cellular mosaic once the production of hair cells and supporting cells is completed. Our results have implications for the proposed used of Notch pathway inhibitors in hearing restoration therapies.
dc.format.extent14
dc.identifier.citationMaass JC, Gu R, Basch ML, Waldhaus J, Lopez EM, Xia A, Oghalai JS, Heller S, Groves AK. Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea. Front Cell Neurosci. 2015 Mar 31;9:110.
dc.identifier.urihttp://hdl.handle.net/11447/1200
dc.identifier.urihttp://dx.doi.org/10.3389/fncel.2015.00110
dc.language.isoen_US
dc.publisherFrontiers Research Foundation
dc.subjectnotch
dc.subjecthair cell
dc.subjectsupporting cell
dc.subjectcochlea
dc.subjectregeneration
dc.titleChanges in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea
dc.typeArtículo

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