J. Exp. Med., Volume 188, Number 12, December 21, 1998 2215-2224

The Transcription Factor Early Growth Response 1 (Egr-1) Advances Differentiation of Pre-B and Immature B Cells

By 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.

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