title: Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals.
abstract: Pre-B cell receptor (pre-BCR) signaling and migration from IL-7-rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C' stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Igκ germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7-dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C' and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique UMR7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Beate
authors.initials: B
authors.lastname: Heizmann
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002469:Cell Separation; D015536:Down-Regulation; D005434:Flow Cytometry; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D015851:Interleukin-7 / Q000378:metabolism*; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D011995:Recombination, Genetic; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D059467:Transcriptome; D045567:VDJ Recombinases / Q000378:metabolism
chemical_list: D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D015851:Interleukin-7; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D045567:VDJ Recombinases