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

• DOI: 10.1038/ni.1667
• Publication Date: 2008-11-02T19:22:07Z
• Authors: Hart S Dengler; Gisele V Baracho; Sidne A Omori; Shane Bruckner; Karen C Arden; Diego H Castrillon; Ronald A DePinho; Robert C Rickert
• Keywords: Homeodomain Proteins; 0301 basic medicine; B-Lymphocytes; Transcription, Genetic; Forkhead Box Protein O1; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Gene Expression; Cell Differentiation; Enzyme-Linked Immunosorbent Assay; Forkhead Transcription Factors; Flow Cytometry; Immunohistochemistry; Mice, Mutant Strains; DNA-Binding Proteins; Blotting, Southern; Mice; 03 medical and health sciences; Animals; Gene Rearrangement, B-Lymphocyte

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-alpha. 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.