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Departments of
* Microbiology, Immunology, and
Molecular Genetics, Sanders Brown Center on Aging,
Graduate Center for Toxicology, and
Markey Cancer Center, University of Kentucky, Lexington, KY 40536;
¶ Basic Science Division, Fox Chase Cancer Center, Philadelphia, PA 19111; and
|| Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Egr-1 (early growth response gene-1) is an immediate early gene encoding a zinc finger motif-containing transcription factor. Upon cross-linking of BCR, mature B cells undergo proliferation with an increase in Egr-1 message. Immature B lymphoma cells that express Egr-1 message and protein constitutively are growth inhibited when Egr-1 is down-regulated by negative signals from BCR or by antisense oligonucleotides. To test the hypothesis that Egr-1 is important for B cell development, we examined B cells from primary and secondary lymphoid organs in Egr-1–/– mice. Marginal zone B cell development was arrested in these mice, whereas the B cells in all other compartments were increased. To test the hypothesis that Egr-1 function may be partially compensated by other Egr family members, we developed transgenic mice expressing a dominant negative form of Egr-1, which lacks the trans activation domain but retains the DNA-binding domain, in a B cell-specific manner. There was a decrease in B lymphopoiesis in the bone marrow accompanied by a reduction in splenic immature and mature B cells as well as marginal zone B cells in the transgenic mice. Moreover, transgenic mice respond poorly to BCR cross-linking in vitro and T-independent and T-dependent Ags in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI 21490, AG 05731, and CA 92372 (to S.B.).
2 Current address: Department of Pathology, Emory University, 1462 Clifton Road N.E., DSB 405, Atlanta, GA 30322.
3 Current address: Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064.
4 Address correspondence and reprint requests to Dr. Subbarao Bondada, Room 303 Combs Cancer Building, Markey Cancer Research Center, University of Kentucky, Lexington, KY 40536-0096. E-mail address: bondada{at}email.uky.edu
5 Abbreviations used in this paper: CBP, cAMP-responsive element-binding protein; DN, dominant negative; MZ, marginal zone; TNP, trinitrophenyl; CLP, common lymphoid progenitors; EBF, early B cell transcription factor; DL1, delta-like 1; PFC, plaque-forming cell.
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