Figure 3.

Signaling events downstream of IL7R (depicted in purple) and the pre-BCR (depicted in black and red) involved in the regulation of RAG1/2 expression and Ig light chain recombination. Coordinate signaling through the IL7 receptor (IL7R) and the pre B-cell receptor (pre-BCR) regulate the expression of the recombination activating gene 1/2 complex (RAG1/2) and immunoglobulin light chain (IgL) recombination in pre-B cells. The IL7R and the pre-BCR have opposing functions in pre-B cells. Engagement of the IL7R results in activation of signal transducer and activator of transcription 5 (STAT5) that promotes proliferation and survival by driving the expression of cyclin D3 (CCND3), and the anti-apoptotic genes BCL2 and MCL1. Simultaneously, IL7R signaling activates the phosphoinositide 3-kinase (PI3K) and AKT, which negatively regulates the forkhead box O1 (FOXO1) transcription factor that is required for RAG1/2 expression and the expression of the apoptotic BIM gene. In addition, IgL accessibility is inhibited by STAT5. Signaling through the pre-BCR activates the RAS and extracellular signal-regulated kinase (ERK) pathway, which induces TCF3 expression (E2A) and represses CCND3. E2A binds and increases the accessibility of the IgLκ locus. Arrows represent positive regulation (activation); T-bars represent negative regulation (inhibition).