Transient Notch Activation Initiates an Irreversible Switch from Neurogenesis to Gliogenesis by Neural Crest Stem Cells

Abstract

The genesis of vertebrate peripheral ganglia poses the problem of how multipotent neural crest stem cells (NCSCs) can sequentially generate neurons and then glia in a local environment containing strong instructive neurogenic factors, such as BMP2. Here we show that Notch ligands, which are normally expressed on differentiating neuroblasts, can inhibit neurogenesis in NCSCs in a manner that is completely dominant to BMP2. Contrary to expectation, Notch activation did not maintain these stem cells in an uncommitted state or promote their self-renewal. Rather, even a transient activation of Notch was sufficient to cause a rapid and irreversible loss of neurogenic capacity accompanied by accelerated glial differentiation. These data suggest that Notch ligands expressed by neuroblasts may act positively to instruct a cell-heritable switch to gliogenesis in neighboring stem cells.

High delta‐like 1 expression in a subset of neuroblastoma cell lines corresponds to a differentiated chromaffin cell type

“…They develop in a spatio-temporal controlled way, which is strongly dependent on Notch signalling. 10 Initially, neurogenic factors such as BMP2 induce differentiation of subsets of stem cells into neurons. These differentiating neurons start to express Delta-family members on their cell surface.…”

“…As a result, these stem cells then switch to differentiate into Schwann cells, instead of neurons. 10 In general, the Delta-Notch pathway functions when 1 precursor cell has to differentiate into 2 different cell lineages. During development of the sympatho-adrenal lineage, precursor neuroblasts can develop into either sympathetic neurons or chromaffin cells.…”

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…Notch signaling promotes the generation of a number of glial cells in the CNS and in vitro experiments have indicated a comparable function for Notch in Schwann cell development (e.g. Morrison et al, 2000;reviewed in Wang and Barres, 2000). In embryonic nerves, Notch signaling correctly times the generation of immature Schwann cells from SCPs in vivo, and controls Schwann cell proliferation (Woodhoo et al, 2007).…”

Development of the Schwann cell lineage: From the neural crest to the myelinated nerve

“…If this was the case, it is plausible that the cells that retain contact with axons would proceed to give rise to Schwann cells, which is in agreement with all the observations that show the requirement for axonal signals in Schwann cell generation (see above). In addition, it is likely that these axonal signals would suppress the differentiation of these SCPs into endoneurial fibroblasts because two of these signals, NRG1 and Notch, have already been shown to suppress the generation of fibroblast-like cells in the neural crest lineage (Morrison et al, 2000;Shah et al, 1994). Those SCPs that are not associated with axons would not be exposed to these signals and their differentiation to fibroblasts would not be inhibited.…”