Developmental changes in Notch1 and numb expression mediated by local cell-cell interactions underlie progressively increasing delta sensitivity in neural crest stem cells.
Neural stem cells become progressively less neurogenic and more gliogenic with development. Here, we show that between E10.5 and E14.5, neural crest stem cells (NCSCs) become increasingly sensitive to the Notch ligand Delta-Fc, a progliogenic and anti-neurogenic signal. This transition is correlated with a 20- to 30-fold increase in the relative ratio of expression of Notch and Numb (a putative inhibitor of Notch signaling). Misexpression experiments suggest that these changes contribute causally to increased Delta sensitivity. Moreover, such changes can occur in NCSCs cultured at clonal density in the absence of other cell types. However, they require local cell-cell interactions within developing clones. Delta-Fc mimics the effect of such cell-cell interactions to increase Notch and decrease Numb expression in isolated NCSCs. Thus, Delta-mediated feedback interactions between NCSCs, coupled with positive feedback control of Notch sensitivity within individual cells, may underlie developmental changes in the ligand-sensitivity of these cells.
Kubu
Chris J
CJ
Laboratory of Neural Stem Cell Biology, John P. Robarts Research Institute, 100 Perth Drive, London Ontario, N6A5K8, Canada.
Orimoto
Kenji
K
Morrison
Sean J
SJ
Weinmaster
Gerry
G
Anderson
David J
DJ
Verdi
Joseph M
JM
D000818:Animals; D002450:Cell Communication; D002999:Clone Cells; D005314:Embryonic and Fetal Development; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D008565:Membrane Proteins / Q000235:genetics*; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009432:Neural Crest / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D051381:Rats; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors; D014162:Transfection
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C497763:Notch1 protein, rat; C106293:Numb protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors