Notch activation instructs rapid glial differentiation by multipotent neural crest stem cells

Abstract

Notch activation has been widely observed to regulate cell fate determination in the nervous system by transiently inhibiting neuronal differentiation, causing progenitors to remain undifferentiated. As expected, Notch activation inhibited neuronal differentiation by neural crest cells in vivo. To study the mechanism we examined the effect of a soluble Notch accurst, Delta-Fc, on neural crest stem cells (NCSCs) that had been isolated by flow-cytometry. Surprisingly, rather than maintaining these stem cells in an uncommitted state, Delta-Fe instructively promoted Schwann (glial) cell differentiation at the expense of neuronal and myofibroblast fates. Delta-Fe increased not only the extent but also the rate of glial marker expression, suggesting that it acts positively as a differentiation-inducing signal. Induction of glial differentiation by Notch was completely dominant to neuronal differentiation induced by the instructive factor BMP2. These data suggest that expression of Notch ligands by differentiating neuroblasts can override BMP2-Induced neurogenesis and promote gliaI differentiation in neighboring cells. Thus, Notch ligand expression may be the switch that ends neuronal differentiation and initiates glial differentiation by neural crest progenitors in developing peripheral nervous system ganglia. More generally, these data suggest, that Notch can act positively as a differentiation-inducing signal for multipotent stem cells.

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