2 Role of RAG1 and RAG2 in B-cell development | 33 tion. The proliferative signals resulting from IL7R/STAT5 activation, mediated through the MAPK pathway, result in FOXO1 inhibition, which also keeps the expression of Rag1 and Rag2 low152. In addition, the extracellular signal-regulated kinase (ERK)/ mitogen-activated protein kinase (MAPK) pathway also regulates E2A (also known as TCF3), which is a RAG transcription factor and a regulator of Ig light chain accessibility 153,154. Figure 3. (A) Schematic representation of the interplay between IL7R signaling and pre-BCR signaling. The signals from IL7R activate PI3K/AKT, which on the one hand negatively regulates Rag1/2 transcription factor FOXO1, and on the other hand activates NF-kB, which in turn further suppresses RAG expression. Moreover, the IL7 signals activate the JAK/STAT5 pathway, which in turn leads to the upregulation of anti-apoptotic proteins, such as Bcl2 or Bcl-XL, but also to the upregulation of CyclinD3 which drives cell proliferation. The pre-BCR counteracts many of the IL7R-driven signals. For instance, AKT signaling is inhibited through pre-BCR-driven B-cell linker (BLNK) upregulation. BLNK also drives the expression of interferon regulatory factor 4 (IRF4), which helps to counteract the IL7R-mediated proliferative signals through Aiolos and Ikaros. IRF4 also increases Ig light chain availability and promotes the binding of RAG1/2 transcription factor E2A to the RAG promoter. The pre-BCR driven extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) signals further aid to counteract the IL7R proliferative and pro-survival signals. (B) Schematic representation of BCR-mediated signals regulating RAG expression. Tonic BCR signaling activates the PI3K/AKT pathway, leading to the downregulation of the RAG1/2 transcription factors FOXO1 and FOXO3. Antigen-dependent BCR signaling activates NF-kB, which conveys the pro-survival and proliferation signals. Created with BioRender.com pre-BCR signaling Following the successful V- to (D)J- recombination at the heavy chain (HC), resulting in the expression of mHC, giving rise to the pre-B cell receptor (pre-BCR), composed of mHC
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