Early B-cell factor 1 regulates the expansion of B-cell progenitors in a dose-dependent manner.
Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2Rα-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1(+/-) pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development.
From the Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty for Health Sciences, Linköping University, University Lab 1, Level 13, SE-581 85 Linköping, Sweden.
Josefine
J
Åhsberg
Jonas
J
Ungerbäck
Tobias
T
Strid
Eva
E
Welinder
Jenny
J
Stjernberg
Malin
M
Larsson
Hong
H
Qian
Mikael
M
Sigvardsson
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D051757:PAX5 Transcription Factor; D011947:Receptors, Antigen, B-Cell; D015534:Trans-Activators; C489921:Ebf1 protein, mouse; C508018:Il2ra protein, mouse; C497282:Pax5 protein, mouse; C075668:Tcf3 protein, mouse
Development; Differentiation; Immunology; Lymphocyte; Transcription Factors