title: FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination.
abstract: Somatic rearrangement of immunoglobulin (Ig) genes is a key step during B cell development. Using pro-B cells lacking the phosphatase Pten (phosphatase and tensin homolog), which negatively regulates phosphoinositide-3-kinase (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 down-regulation 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 V(H) to DJ(H) gene rearrangement. Simultaneous expression of the transcription factor Pax5 was needed for the activation of distal V(H) 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 V(H) to DJ(H) gene rearrangement downstream of FoxO1 and cooperates with Pax5 to activate the rearrangement of distal V(H) genes.
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, Albert-Ludwigs University of Freiburg and Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Alabbas
authors.initials: A
authors.lastname: Alkhatib
authors.forename: Markus
authors.initials: M
authors.lastname: Werner
authors.forename: Eva
authors.initials: E
authors.lastname: Hug
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herzog
authors.forename: Cathrin
authors.initials: C
authors.lastname: Eschbach
authors.forename: Hemin
authors.initials: H
authors.lastname: Faraidun
authors.forename: Fabian
authors.initials: F
authors.lastname: Köhler
authors.forename: Thomas
authors.initials: T
authors.lastname: Wossning
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005803:Genes, Immunoglobulin / Q000235:genetics*; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D051757:PAX5 Transcription Factor / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D012326:RNA Splicing / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D060152:V(D)J Recombination / Q000502:physiology*
chemical_list: D017931:DNA Primers; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse