| The Foxo transcription factors modulate cell fate decisions in diverse systems. Although B-cells express Foxo1, Foxo3 and Foxo4, the importance of individual Foxo members in B-cells is unclear. Here we show that Foxo1 and Foxo3 are not redundant in their roles in B cell development and activation. Foxo1 is shown to play a critical unique role at three stages of B-cell differentiation. Early deletion of Foxo1 causes a severe block at the pro-B cell stage, due to impaired expression of genes involved in B cell development including Pu.1, E2A, and EBF. In addition Foxo1 regulates IL-7R expression blocking cell survival of Foxo1 deficient pro-B cells. Foxo1 inactivation in late pro-B cells results in an arrest at the cycling pre-B cell stage due to a reduction in Rag1/Rag2 expression and subsequent block in recombination of the immunoglobulin loci. Foxo1 inactivation in transitional B-cells leads to alterations in B1 cell differentiation but normal marginal zone development. In addition, Foxo1 inactivation leads to failed class switch recombination due to impaired Aicda upregulation. Thus, Foxo1 uniquely regulates a transcriptional program that is essential for early B-cell development and peripheral B-cell function. |
