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Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation

Abstract

The transcription factors Foxo1, Foxo3 and Foxo4 modulate cell fate 'decisions' in diverse systems. Here we show that Foxo1-dependent gene expression was critical at many stages of B cell differentiation. Early deletion of Foxo1 caused a substantial block at the pro–B cell stage due to a failure to express interleukin 7 receptor-α. Foxo1 inactivation in late pro–B cells resulted in an arrest at the pre–B cell stage due to lower expression of the recombination-activating genes Rag1 and Rag2. Deletion of Foxo1 in peripheral B cells led to fewer lymph node B cells due to lower expression of L-selectin and failed class-switch recombination due to impaired upregulation of the gene encoding activation-induced cytidine deaminase. Thus, Foxo1 regulates a transcriptional program that is essential for early B cell development and peripheral B cell function.

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Figure 1: Foxo1 directs the development of pro–B cells.
Figure 2: Foxo1 regulates IL-7Rα expression and pro–B cell survival.
Figure 3: Foxo1 regulates RAG expression to induce rearrangement of immunoglobulin genes.
Figure 4: Foxo1 regulates the rearrangement of immunoglobulin κ-chain genes in pre–B cells.
Figure 5: Foxo1L/LCd21Cre mice have fewer lymph node and peritoneal B-1a cells.
Figure 6: Foxo1L/LCd21Cre B cells have impaired responses to anti-IgM stimulation in vitro but have intact antibody responses to TI-2 antigens.
Figure 7: Foxo1 is required for CSR but not germinal center formation.
Figure 8: Foxo1 regulates AID expression.

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Acknowledgements

We thank K. Rajewsky (Harvard University) and M. Reth (Max-Planck Institute) for Cd21Cre and mb1Cre mice, respectively; B. Finlay (Burnham Institute for Medical Research) and K. Mowen (The Scripps Research Institute) for retroviruses expressing Bcl-xL and Cre, respectively; and S. Hedrick and members of the Rickert laboratory for discussions and reading of the manuscript. Supported by the US National Institutes of Health (AI059447 to R.C.R.), the American Cancer Society (R.A.D.) and the Robert A. and Renee E. Befler Foundation Institute for Innovative Cancer Science (R.A.D.).

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H.S.D. designed and did experiments, analyzed data and wrote the manuscript; G.V.B. and S.A.O. designed and did experiments, provided experimental advice and revised the manuscript; S.B. contributed to experiments; D.H.C., R.A.D. and K.C.A. provided mice; and R.C.R. supervised the research and wrote the manuscript.

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Correspondence to Robert C Rickert.

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Dengler, H., Baracho, G., Omori, S. et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat Immunol 9, 1388–1398 (2008). https://doi.org/10.1038/ni.1667

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