Figure 5. Regulatory network orchestrating the pre-B cell developmental checkpoint.

There are a series of feedforward and feedback regulatory loops between the interleukin-7 receptor (IL-7R) and the pre-B cell receptor (pre-BCR) that ensure dominance of one receptor at a given time. Downstream of the IL-7R, activation of phosphoinositide 3-kinase (PI3K) destabilizes both forkhead box protein O1 (FOXO1) and paired box 5 (PAX5). In addition to regulating recombination-activating gene 1 (RAG1) and RAG2 expression, both transcription factors are needed for optimal expression of spleen tyrosine kinase (SYK) and B cell linker protein (BLNK), a central signalling module of the pre-BCR. FOXO1 and PAX5 are also necessary for the induction of interferon-regulatory factor 4 (IRF4) expression through SYK–BLNK signalling. Thus, in the presence of IL-7R signalling, the pre-BCR cannot fully couple to important downstream signalling targets that are necessary for the induction of Igκ gene recombination. After a pre-B cell has attenuated or escaped IL-7R signalling thereby enabling efficient coupling of the SYK–BLNK module to the pre-BCR, regulatory loops are engaged that further repress the IL-7R and reinforce the mechanisms of recombination. The SYK–BLNK module feeds back to repress PI3K and AKT activation, and BLNK induces activation of the mitogen-activated protein kinase p38, which phosphorylates and augments FOXO1 activity. Activated FOXO1 further enhances signalling through the pre-BCR, the induction of RAG1 and RAG2 expression and commitment to Igκ gene recombination. FOXO1 also feeds back to repress IL-7Rα expression. The thick black arrows represent primary pre-BCR signalling cascades, whereas the thin black arrows denote feedforward loops. The thick red arrows represent the negative regulatory pathways through which the pre-BCR inhibits IL-7R signalling.