Article abstract
Nature Immunology 10, 1110 - 1117 (2009)
Published online: 6 September 2009 | doi:10.1038/ni.1785
Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development
Malay Mandal1, Sarah E Powers1, Kyoko Ochiai2, Katia Georgopoulos3, Barbara L Kee4, Harinder Singh2 & Marcus R Clark1
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 
-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.
- Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, Illinois, USA.
- Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, USA.
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
- Department of Pathology, University of Chicago, Chicago, Illinois, USA.
Correspondence to: Marcus R Clark1 e-mail: mclark@medicine.bsd.uchicago.edu
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