In pro-B cells, IL-7 promotes cell cycle progression ( Clark et al., 2014) and the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 suppress proliferation, allowing Igh chain recombination and B cell development ( Galloway et al., 2016).
These include B cell translocation gene 2 (BTG2) and protein arginine methyl transferase 1 (PRMT1) ( Dolezal et al., 2017), the signal transducers RAS ( Mandal et al., 2009) and dual specificity tyrosine-regulated kinase 1A (DYRK1A) ( Thompson et al., 2015) and the transcription factors interferon regulatory factor-4 and −8 (IRF4, IRF8) ( Lu et al., 2003), IKAROS and AIOLOS ( Ma et al., 2010), BCL-6 ( Nahar et al., 2011) and FOXO3a ( Herzog et al., 2008). Several factors have been identified that suppress proliferation in late-pre-B cells and allow Igl recombination. The alternation between proliferative and non-proliferative stages during B cell development is precisely controlled to maintain genomic integrity ( Herzog et al., 2009 Clark et al., 2014). V(D)J recombination occurs during the G0/G1 phase of the cell cycle ( Schlissel et al., 1993) and the RAG proteins, which are essential for V(D)J recombination, are degraded upon entry into S-phase, suppressing further recombination ( Li et al., 1996). Successful VDJ recombination of the Igh chain locus is coupled with a rapid proliferative expansion of early-pre-B cells (FrC’) and the subsequent return to quiescence permissive for recombination at the Igl chain loci in late-pre-B cells (FrD) ( Herzog et al., 2009). Pro-B cells can be separated into fractions (Fr) B and C according to Hardy’s criteria ( Hardy et al., 1991), with D to J gene segment recombination occurring in FrB pro-B cells prior to V to DJ recombination in FrC pro-B cells ( Hardy and Hayakawa, 2003). Igh-recombination at the pro-B cell stage typically occurs before Igl recombination in B cell ontogeny ( Figure 1-figure supplement 1A).
Antibody diversity is crucial to fight infections and is generated throughout B cell development by the orderly recombination of V(D)J gene segments of the immunoglobulin heavy (Igh) and light (Igl) chain loci.
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