title: Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors.
abstract: To investigate how transcription factor levels impact B-lymphocyte development, we generated mice carrying transheterozygous mutations in the Pax5 and Ebf1 genes. Whereas combined reduction of Pax5 and Ebf1 had minimal impact on the development of the earliest CD19(+) progenitors, these cells displayed an increased T cell potential in vivo and in vitro. The alteration in lineage fate depended on a Notch1-mediated conversion process, whereas no signs of de-differentiation could be detected. The differences in functional response to Notch signaling in Wt and Pax5(+/-)Ebf1(+/-) pro-B cells were reflected in the transcriptional response. Both genotypes responded by the generation of intracellular Notch1 and activation of a set of target genes, but only the Pax5(+/-)Ebf1(+/-) pro-B cells down-regulated genes central for the preservation of stable B cell identity. This report stresses the importance of the levels of transcription factor expression during lymphocyte development, and suggests that Pax5 and Ebf1 collaborate to modulate the transcriptional response to Notch signaling. This provides an insight on how transcription factors like Ebf1 and Pax5 preserve cellular identity during differentiation.
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linköping, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ungerbäck
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linköping, Sweden.
authors.forename: Josefine
authors.initials: J
authors.lastname: Åhsberg
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linköping, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strid
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linköping, Sweden.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Somasundaram
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linköping, Sweden mikael.sigvardsson@liu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D019656:Loss of Heterozygosity; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013601:T-Lymphocytes / Q000166:cytology*; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
chemical_list: D018941:Antigens, CD19; D017931:DNA Primers; C489921:Ebf1 protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D051880:Receptors, Notch; D015534:Trans-Activators