Figure 1. Integration of surface receptor signals and DNA damage responses in pre-B cells. In developing pre-B cells, signals from the IL-7r, pre-BCR and RAG DSBs coordinate to direct continued maturation. In large pre-B cells, IL-7r and pre-BCR signals support proliferation and survival to optimize clonal expansion of IgH-expressing cells. This proliferation phase occurs in bone marrow niches rich in IL-7-producing cells. IL-7r signals through STAT5 and Akt to maintain proliferation and survival. Additionally, STAT5 supports IgH chain gene transcription and suppresses IgL chain gene accessibility while Akt inhibits RAG expression. Pre-BCR signals support Akt signaling during this expansion phase. Attenuation of IL-7r signaling, which may be mediated by migration of pre-B cells to bone marrow niches devoid of IL-7-producing cells, results in transition to the small pre-B cell developmental stage. Loss of IL-7 results in termination of STAT5 signals and associated cell cycle arrest. The cessation of Akt activity results in stabilization of FoxO transcription factors and expression of RAG and SLP-65. SLP-65 redirects pre-BCR signaling to expression of IRF4 and transcription of IgL chain genes, which permits IgL locus accessibility to RAG. RAG DSBs trigger ATM-dependent DNA damage responses (DDR), which intersect with pre-BCR signals to promote pre-B cell survival, suppress IL-7-driven proliferation and trigger expression of proteins that support cellular re-localization.