Abstract
Signals through the pre–B cell antigen receptor (pre-BCR) and interleukin 7 receptor (IL-7R) coordinate pre–B cell population expansion with subsequent recombination of the locus encoding immunoglobulin κ-chain (Igk). Although many 'downstream' effectors of each receptor are known, how they integrate to mediate development has remained unclear. Here we report that pre-BCR-mediated activation of the Ras-MEK-Erk signaling pathway silenced transcription of Ccnd3 (encoding cyclin D3) and coordinated exit from the cell cycle with induction of the transcription factor E2A and the initiation of Igk recombination. IL-7R-mediated activation of the transcription factor STAT5 opposed this pathway by promoting Ccnd3 expression and concomitantly inhibiting Igk transcription by binding to the Igk intronic enhancer and preventing E2A recruitment. Our data show how pre-BCR signaling poises pre–B cells to undergo differentiation after escape from IL-7R signaling.
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Acknowledgements
We thank T. Gajewski (University of Chicago) for cDNA encoding CA-Ras, CA-STAT5B and DN-Ras; N.G. Ahn (University of Colorado, Boulder) for cDNA encoding DN-MEK; M. Veselits for technical assistance; R. Duggan and D. Leclerc for cell-sorting services; and F. Gounari for discussions.
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M.M. designed, did, interpreted and prepared figures of most experiments and assisted in preparing the initial manuscript; S.E.P. assisted in the design and analysis of many experiments; K.O. assisted with chromatin immunoprecipitation; K.G. provided Aiolos-specific reagents and scientific advice and assisted in preparing the manuscript; B.L.K. provided E2A-specific reagents, contributed to the design of some experiments, provided scientific advice and edited the manuscript; H.S. assisted in establishing many of the experimental systems, provided substantial scientific input and edited the final manuscript; and M.R.C. oversaw the entire project and prepared the final manuscript.
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Mandal, M., Powers, S., Ochiai, K. et al. Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development. Nat Immunol 10, 1110–1117 (2009). https://doi.org/10.1038/ni.1785
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DOI: https://doi.org/10.1038/ni.1785
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