Ikawa Tomokatsu, Kawamoto Hiroshi, Goldrath Ananda W, Murre Cornelis
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
J Exp Med. 2006 May 15;203(5):1329-42. doi: 10.1084/jem.20060268. Epub 2006 May 8.
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 hematopoietic 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.
螺旋-环-螺旋蛋白E47对B细胞和T细胞谱系的发育至关重要。在此我们证明，在体外，E47和Notch信号协同作用，促进胎儿造血祖细胞向T细胞发育，并抑制向自然杀伤细胞和髓系细胞谱系的发育。与Notch信号相关的一组基因的表达被E47激活，此外，Notch信号和E47在平行途径中发挥作用，以诱导T细胞谱系特异性基因表达程序。Notch细胞内结构域的强制表达挽救了E2A缺陷型胎儿胸腺细胞在T细胞定向阶段的发育停滞。最后，我们证明Notch信号和E47对Hes1表达的调控与在黑腹果蝇感觉发育过程中观察到的调控惊人地相似。基于这些观察结果，我们提出，在发育中的胎儿胸腺细胞中，E47诱导参与Notch信号的一组基因的表达，随后E47与Notch信号平行发挥作用，促进T细胞谱系成熟。
