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Adelheid Dinkel^*, Klaus Warnatz^*, Birgit Ledermann, Antonius Rolink, Peter F. Zipfel^||, Kurt Bürki, and Hermann Eibel^*

From the ^* Clinical Research Unit for Rheumatology, Division of Rheumatology and Clinical Immunology, University Hospital Freiburg, D-79106 Freiburg, Germany; Preclinical Research, Novartis Ltd., CH-4002 Basel, Switzerland; Basel Institute for Immunology, CH-4058 Basel, Switzerland; and the ^|| Bernhard-Nocht-Institute for Tropical Medicine, D-20359 Hamburg, Germany

In mature B lymphocytes, the zinc finger transcription factor early growth response 1 (Egr-1) is one of the many immediate-early genes induced upon B cell antigen receptor engagement. However, its role during earlier stages of lymphopoiesis has remained unclear. By examining bone marrow B cell subsets, we found Egr-1 transcripts in pro/pre-B and immature B lymphocytes, and Egr-1 protein in pro/pre-B–I cells cultivated on stroma cells in the presence of interleukin (IL)-7. In recombinase-activating gene (RAG)-2–deficient mice overexpressing an Egr-1 transgene in the B lymphocyte lineage, pro/pre-B–I cells could differentiate past a developmental block at the B220^low BP-1^– stage to the stage of B220^low BP-1⁺ pre-B–I cells, but not further to the B220^low BP-1⁺ CD25⁺ stage of pre-B–II cells. Therefore, during early B lymphopoiesis progression from the B220^low BP-1^– IL-2R^– pro/pre-B–I stage to the B220^low BP-1⁺ IL-2R⁺ pre-B–II stage seems to occur in at least two distinct steps, and the first step to the stage of B220^low BP-1⁺ pre-B–I cells can be promoted by the overexpression of Egr-1 alone. Wild-type mice expressing an Egr-1 transgene had increased proportions of mature immunoglobulin (Ig)M⁺ B220^high and decreased proportions of immature IgM⁺ B220^low bone marrow B cells. Since transgenic and control precursor B cells show comparable proliferation patterns, overexpression of Egr-1 seems also to promote entry into the mature B cell stage. Analysis of changes in the expression pattern of potential Egr-1 target genes revealed that Egr-1 enhances the expression of the aminopeptidase BP-1/6C3 in pre-B and immature B cells and upregulates expression of the orphan nuclear receptor nur77 in IgM⁺ B cells.

Key Words: Egr-1 • transcription factor • B cell development • BP-1 • nur77

Part of this work was supported through Deutsche Forschungsgemeinschaft grants Ei235/3-1 and Ei235/4-1 (to H. Eibel).

Abbreviations used: BCR, B cell antigen receptor; BrdU, bromodeoxyuridine; Egr-1, early growth response 1; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal–regulated kinase; RAG, recombinase-activating gene.

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