Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development

• Published in: Nature immunology Vol. 10; no. 10; pp. 1110 - 1117
• Main Authors: Ochiai, Kyoko, Mandal, Malay, Georgopoulos, Katia, Singh, Harinder, Clark, Marcus R, Powers, Sarah E, Kee, Barbara L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-10-2009; Nature Publishing Group
• Subjects: Animals; B cells; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Basic Helix-Loop-Helix Transcription Factors - immunology; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biomedical and Life Sciences; Biomedicine; Cell cycle; Cell Cycle - genetics; Cell Cycle - immunology; Cell Differentiation - immunology; Cyclin D3; Cyclins - immunology; Cyclins - metabolism; Electrophoretic Mobility Shift Assay; Extracellular Signal-Regulated MAP Kinases - immunology; Flow Cytometry; Gene Expression Regulation - immunology; Gene Silencing - immunology; Immunoblotting; Immunoglobulin Light Chains - genetics; Immunoglobulins; Immunology; Infectious Diseases; MAP Kinase Kinase Kinases - immunology; Mice; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Physiological aspects; Population growth; ras Proteins - genetics; ras Proteins - immunology; ras Proteins - metabolism; Receptors, Interleukin-7 - immunology; Receptors, Interleukin-7 - metabolism; Recombination, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - immunology; STAT5 Transcription Factor - immunology; STAT5 Transcription Factor - metabolism; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.1785

How signals through the pre–B cell antigen receptor (pre-BCR) and IL-7 receptor (IL-7R) coordinate population expansion of pre-B cells with subsequent recombination of the immunoglobulin κ-chain locus is unclear. Clark and colleagues show that pre-BCR signaling via the Ras-MEK-Erk pathway poises pre–B cells to undergo differentiation after escaping IL-7R signaling.
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.