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RESEARCH PAPER
1 Division of Biology, California Institute of Technology, Pasadena, California 91125, USA; 2 Department of Immunology, University of Toronto, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada
Using the OP9-DL1 system to deliver temporally controlled Notch/Delta signaling, we show that pluripotent hematolymphoid progenitors undergo T-lineage specification and B-lineage inhibition in response to Notch signaling in a delayed and asynchronous way. Highly enriched progenitors from fetal liver require 
3 d to begin B- or T-lineage differentiation. Clonal switch-culture analysis shows that progeny of some single cells can still generate both B- and T-lineage cells, after 1 wk of continuous delivery or deprivation of Notch/Delta signaling. Notch signaling induces T-cell genes and represses B-cell genes, but kinetics of activation of lineage-specific transcription factors are significantly delayed after induction of Notch target genes and can be temporally uncoupled from the Notch response. In the cells that initiate T-cell differentiation and gene expression most slowly in response to Notch/Delta signaling, Notch target genes are induced to the same level as in the cells that respond most rapidly. Early lineage-specific gene expression is also rapidly reversible in switch cultures. Thus, while necessary to induce and sustain T-cell development, Notch/Delta signaling is not sufficient for T-lineage specification and commitment, but instead can be permissive for the maintenance and proliferation of uncommitted progenitors that are omitted in binary-choice models.
[Keywords: GATA-3; hematopoietic progenitor cells; lineage commitment; lymphocyte development; Pax-5; transcription factors]
Received January 14, 2005; revised version accepted March 8, 2005.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1298305.
3 Corresponding author.
E-MAIL evroth{at}its.caltech.edu; FAX (626) 449-0756.
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