Early thymocyte development is regulated by modulation of E2A protein activity

The E2A gene encodes the E47 and E12 basic helix-loop-helix (bHLH) transcri ption factors. T cell development in E2A-deficient mice is partially arrest ed before lineage commitment. Here we demonstrate that E47 expression becom es uniformly high at the point at which thymocytes begin to commit towards the T cell lineage. E47 protein levels remain high until the double positiv e developmental stage, at which point they drop to relatively moderate leve ls, and are further downregulated upon transition to the single positive st age. However, stimuli that mimic pre-T cell receptor (TCR) signaling in com mitted T cell precursors inhibit E47 DNA-binding activity and induce the bH LH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependen t pathway. Consistent with these observations, a deficiency in E2A proteins completely abrogates the developmental block observed in mice with defects in TCR rearrangement. Thus E2A proteins are necessary for both initiating T cell differentiation and inhibiting development in the absence of pre-TCR expression. Mechanistically, these data link pre-TCR mediated signaling an d E2A downstream target genes into a common pathway.