Notch Signaling Alters Sensory or Neuronal Cell Fate Specification of Inner Ear Stem Cells

Abstract

Multipotent progenitor cells in the otic placode give rise to the specialized cell types of the inner ear, including neurons, supporting cells and hair cells. The mechanisms governing acquisition of specific fates by the cells that form the cochleovestibular organs remain poorly characterized. Here we show that whereas blocking Notch signaling with a γ-secretase inhibitor increased the conversion of inner ear stem cells to hair cells by a mechanism that involved the upregulation of bHLH transcription factor, Math1 (mouse Atoh1), differentiation to a neuronal lineage was increased by expression of the Notch intracellular domain. The shift to a neuronal lineage could be attributed in part to the continued cell proliferation in cells that did not undergo sensory cell differentiation due to the high Notch signaling, but also involved upregulation of Ngn1. The Notch intracellular domain influenced Ngn1 indirectly by upregulation of Sox2, a transcription factor expressed in many neural progenitor cells, and directly by an interaction with an RBP-J binding site in the Ngn1 promoter/enhancer. The induction of Ngn1 was blocked partially by mutation of the RBP-J site and nearly completely when the mutation was combined with inhibition of Sox2 expression. Thus Notch signaling had a significant role in the fate specification of neurons and hair cells from inner ear stem cells, and decisions about cell fate were mediated in part by a differential effect of combinatorial signaling by Notch and Sox2 on the expression of bHLH transcription factors.

In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation

“…Gain-and loss-of-function in vitro studies support the signaling hierarchy from NICD to Sox2 to Prox1 (Dabdoub et al, 2008;Jeon et al, 2011). Consistent with these results, our in vivo study also demonstrated that NICD was sufficient to reactivate Sox2 expression but not to induce Prox1, because ectopic Prox1 expression was exclusive to OHCs.…”

Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

“…Notch is essential in defining the prosensory domain in the otocyst and is instrumental in establishing lateral inhibition that determines HC vs. SC fate in the cochlear sensory epithelia (22,42,43). Loss of Notch signaling produces ectopic HCs through direct transdifferentiation of SCs during late development and postnatal cochlea (22)(23)(24)(25), yet the role of Notch in cell proliferation under those conditions remains to be determined.…”

Green Tea Polyphenols Protects Cochlear Hair Cells from Ototoxicity by Inhibiting Notch Signalling

“…Notch signalling pathway is a highly conserved cell signalling system and plays an essential role in controlling the development of cochlea. It has been shown that inactivation of the Notch signalling pathway can promote the proliferation of hair cells [7,[20][21][22]. In the recent studies, more and more scientists devote to explore the targets in Notch signalling pathway to recover the regeneration of damaged hair cells.…”

“…In their studies, Notch signalling pathway exerts lateral inhibition in the development of cochlear mosaic, which plays an important role in the determination of various cell fates. According to the recent studies, inactivation of the Notch signalling pathway can promote the proliferation of hair cells [7,[20][21][22]. Therefore, the inhibitors of c-secrectase might promote the proliferation and regeneration of hair cells in the damaged cochlea by targeting the Notch receptors to suppress the Notch activity [22].…”