FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination.
30.01.2012
Alkhatib A, Werner M, Hug E, Herzog S, Eschbach C, Faraidun H, Köhler F, Wossning T, Jumaa H.
J Exp Med. 2012 Feb 13;209(2):395-406.
Somatic rearrangement of immunoglobulin (Ig) genes is a key step during B cell development. Here, using pro-B cells lacking the phosphatase Pten, which negatively regulates PI3K signaling, we show that PI3K signaling inhibits Ig gene rearrangement by suppressing the expression of the transcription factor Ikaros. Further analysis revealed that the transcription factor FoxO1 is crucial for Ikaros expression and that PI3K-mediated downregulation of FoxO1 suppresses Ikaros expression. Interestingly, FoxO1 did not influence Ikaros transcription; instead, FoxO1 is essential for proper Ikaros mRNA splicing as FoxO1-deficient cells contain aberrantly processed Ikaros transcripts. Moreover, FoxO1-induced Ikaros expression was sufficient only for proximal VH to DJH gene rearrangement. Simultaneous expression of the transcription Pax5 was needed for the activation of distal VH genes; however, Pax5 did not induce any Ig gene rearrangement in the absence of Ikaros. Together, our results suggest that ordered Ig gene rearrangement is regulated by distinct activities of Ikaros, which mediates proximal VH to DJH gene rearrangement downstream of FoxO1 and cooperates with Pax5 to activate the rearrangement of distal VH genes.
