title: IL-7 functionally segregates the pro-B cell stage by regulating transcription of recombination mediators across cell cycle.
abstract: Ag receptor diversity involves the introduction of DNA double-stranded breaks during lymphocyte development. To ensure fidelity, cleavage is confined to the G(0)-G(1) phase of the cell cycle. One established mechanism of regulation is through periodic degradation of the RAG2 recombinase protein. However, there are additional levels of protection. In this paper, we show that cyclical changes in the IL-7R signaling pathway functionally segregate pro-B cells according to cell cycle status. In consequence, the level of a downstream effector of IL-7 signaling, phospho-STAT5, is inversely correlated with cell cycle expression of Rag, a key gene involved in recombination. Higher levels of phopho-STAT5 in S-G(2) correlate with decreased Rag expression and Rag relocalization to pericentromeric heterochromatin. These cyclical changes in transcription and locus repositioning are ablated upon transformation with v-Abl, which renders STAT5 constitutively active across the cell cycle. We propose that this activity of the IL-7R/STAT5 pathway plays a critical protective role in development, complementing regulation of RAG2 at the protein level, to ensure that recombination does not occur during replication. Our data, suggesting that pro-B cells are not a single homogeneous population, explain inconsistencies in the role of IL-7 signaling in regulating Igh recombination.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Julie
authors.initials: J
authors.lastname: Chaumeil
authors.forename: Mariann
authors.initials: M
authors.lastname: Micsinai
authors.forename: Joy M H
authors.initials: JM
authors.lastname: Wang
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.forename: Gisele V
authors.initials: GV
authors.lastname: Baracho
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rickert
authors.forename: Francesco
authors.initials: F
authors.lastname: Strino
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrar
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics / Q000276:immunology; D016654:Genes, RAG-1; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017404:In Situ Hybridization, Fluorescence; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D015851:Interleukin-7; D050799:STAT5 Transcription Factor; C064658:RAG-1 protein