title: A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation.
abstract: The molecular crosstalk between the interleukin 7 receptor (IL-7R) and the precursor to the B cell antigen receptor (pre-BCR) in B lymphopoiesis has not been elucidated. Here we demonstrate that in pre-B cells, the IL-7R but not the pre-BCR was coupled to phosphatidylinositol-3-OH kinase (PI(3)K) and the kinase Akt; signaling by this pathway inhibited expression of recombination-activating gene 1 (Rag1) and Rag2. Attenuation of IL-7 signaling resulted in upregulation of the transcription factors Foxo1 and Pax5, which coactivated many pre-B cell genes, including Rag1, Rag2 and Blnk. Induction of Blnk (which encodes the signaling adaptor BLNK) enabled pre-BCR signaling via the signaling molecule Syk and promoted immunoglobulin light-chain rearrangement. BLNK expression also antagonized Akt activation, thereby augmenting the accumulation of Foxo1 and Pax5. This self-reinforcing molecular circuit seemed to sense limiting concentrations of IL-7 and functioned to constrain the proliferation of pre-B cells and trigger their differentiation.
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ochiai
authors.forename: Mark
authors.initials: M
authors.lastname: Maienschein-Cline
authors.forename: Malay
authors.initials: M
authors.lastname: Mandal
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Triggs
authors.forename: Eric
authors.initials: E
authors.lastname: Bertolino
authors.forename: Roger
authors.initials: R
authors.lastname: Sciammas
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Dinner
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Clark
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology*; D051379:Mice; D051757:PAX5 Transcription Factor / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D015851:Interleukin-7; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D011947:Receptors, Antigen, B-Cell