Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process

Abstract

We examined the role of Notch signaling on the generation of neurons and glia from neural stem cells by using neurospheres that are clonally derived from neural stem cells. Neurospheres prepared from Dll1 lacZ/lacZ mutant embryos segregate more neurons at the expense of both oligodendrocytes and astrocytes. This mutant phenotype could be rescued when Dll1 lacZ/lacZ spheres were grown and/or differentiated in the presence of conditioned medium from wild-type neurospheres. Temporal modulation of Notch by soluble forms of ligands indicates that Notch signaling acts in two steps. Initially, it inhibits the neuronal fate while promoting the glial cell fate. In a second step, Notch promotes the differentiation of astrocytes, while inhibiting the differentiation of both neurons and oligodendrocytes.

Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formation

“…Care and use of experimental animals described in this work comply with guidelines and policies of the University Committee on Animal Resources at the University of Rochester. Isolation and culture of primary neurospheres, NEP, MEC, calvarial MSC, and other cell lines are described in the SI Methods (41)(42)(43)(44). RNA probes (5,25) were generated to analyze the gene expression pattern by in situ hybridization (45).…”

Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents

“…Sequential Notch receptor activation has been suggested to occur during spermatogenesis (Mori et al, 2003) and in ovarian follicles (Johnson et al, 2001). There is strong evidence that Notch signaling participates in mammalian brain development, primarily inhibiting neuronal differentiation and allowing/ promoting glial differentiation (Morrison et al, 2000;Grandbarbe et al, 2003). Expression of Notch in the adult brain has been described (Berezovska et al, 1998;Berezovska et al, 1999), but the postnatal neurological functions of Notch signaling remain largely unexplored.…”

Polypyrimidine tract binding protein and Notch1 are independently re-expressed in glioma

“…The cell fate choice can be manipulated by expressing Notch1 in progenitors to drive astrocytic differentiation and inhibit the default oligodendrocyte pathway. [17][18][19] We examined PTB and Notch1IC levels in these tumor subtypes (Figure 3). No significant differences in PTB expression existed between the two, but there was a trend towards higher levels of PTB in oligodendrocytic tumors.…”

“…In the astrocytic lineage, it directs terminal differentiation of precursors into astrocytes, as opposed to oligodendrocytes. [17][18][19] Activation of Notch is mediated through the binding of membrane-bound ligands, Delta or Serrate/Jagged, located on neighboring cells. The act of ligand binding initiates dissociation of the receptor domains and triggers two cleavages: the extracellular segment by an ADAM metalloproteinase and the intracellular transmembrane by presenilin-dependent proteases.…”