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Published April 1, 2002 | public
Journal Article

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.

Additional Information

© 2002 Elsevier Science. Received for publication November 29, 2001; Accepted December 19, 2001; Published online March 6, 2002. We would like to thank Dr. James MacDonald for their insightful and critical reading of earlier versions of this manuscript. We would also like to thank Kevin Partridge for computer assistance and figure preparation, and Martin White of the John P. Robarts Cell Sorting Facility for his expertise and time. This work was supported in part by grants from the Heart and Stroke Foundation of Ontario (NA4497), the Medical Research Council of Canada (MT-1313), and the Canadian Institute of Health Research (MOP-44035). S.J.M. is a Howard Hughes Associate Investigator, D.J.A. is a Howard Hughes Principal Investigator, and J.M.V. is a scholar of the MRC (now the CIHR) and an EJLB Foundation Scholar.

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