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

Abstract

Foxo transcription factors are linked to complex regulatory circuits governed by the availability of phosphatidylinositol-3,4,5-trisphosphate. Rickert and colleagues show that Foxo1 has nonredundant functions at many stages of B cell development. 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.