Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells.
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.
Morrison
S J
SJ
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
Perez
S E
SE
Qiao
Z
Z
Verdi
J M
JM
Hicks
C
C
Weinmaster
G
G
Anderson
D J
DJ
D000818:Animals; D030161:Avian Proteins; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002642:Chick Embryo; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins; D009432:Neural Crest / Q000166:cytology*; D020890:Neuregulin-1 / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D012995:Solubility; D013234:Stem Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta
D030161:Avian Proteins; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D007141:Immunoglobulin Fc Fragments; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C490582:NRG1 protein, Gallus gallus; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C064045:delta protein; C499469:recombinant human bone morphogenetic protein-2