The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online 8 May 2006 doi:10.1084/jem.20060268
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 5, 1329-1342
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ARTICLE

 E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment

Tomokatsu Ikawa1, Hiroshi Kawamoto2, Ananda W. Goldrath1, and Cornelis Murre1

1 Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093
2 Laboratory for Lymphocyte Development, Riken Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan

CORRESPONDENCE Cornelis Muree: murre{at}biomail.ucsd.edu

The helix-loop-helix protein, E47, is essential for both B- and T-lineage development. Here we demonstrate that in vitro E47 and Notch signaling act in concert to promote T cell development from fetal hematopoieitic progenitors and to restrain development into the natural killer and myeloid cell lineages. The expression of an ensemble of genes associated with Notch signaling is activated by E47, and additionally, Notch signaling and E47 act in parallel pathways to induce a T lineage–specific program of gene expression. Enforced expression of the intracellular domain of Notch rescues the developmental arrest at the T cell commitment stage in E2A-deficient fetal thymocytes. Finally, we demonstrate that regulation of Hes1 expression by Notch signaling and E47 is strikingly similar to that observed during Drosophila melanogaster sensory development. Based on these observations, we propose that in developing fetal thymocytes E47 acts to induce the expression of an ensemble of genes involved in Notch signaling, and that subsequently E47 acts in parallel with Notch signaling to promote T-lineage maturation.

Abbreviations used: 4-OHT, 4-hydroxytamoxifen; ARP, acidic ribosomal protein; bHLH, basic HLH; ChIP, chromatin immunoprecipitation; CLP, common lymphoid progenitor cells; CHX, cycloheximide; DL1, delta-like 1; DN, double negative; DP, double positive; HLH, helix loop helix; HPC, hematopoietic progenitor cell; HSC, hematopoietic stem cell; MAP, mitogen-activated protein.


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