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      Essential control of early B-cell development by Mef2 transcription factors.

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          Abstract

          The sequential activation of distinct developmental gene networks governs the ultimate identity of a cell, but the mechanisms involved in initiating downstream programs are incompletely understood. The pre-B-cell receptor (pre-BCR) is an important checkpoint of B-cell development and is essential for a pre-B cell to traverse into an immature B cell. Here, we show that activation of myocyte enhancer factor 2 (Mef2) transcription factors (TFs) by the pre-BCR is necessary for initiating the subsequent genetic network. We demonstrate that B-cell development is blocked at the pre-B-cell stage in mice deficient for Mef2c and Mef2d TFs and that pre-BCR signaling enhances the transcriptional activity of Mef2c/d through phosphorylation by the Erk5 mitogen-activating kinase. This activation is instrumental in inducing Krüppel-like factor 2 and several immediate early genes of the AP1 and Egr family. Finally, we show that Mef2 proteins cooperate with the products of their target genes (Irf4 and Egr2) to induce secondary waves of transcriptional regulation. Our findings uncover a novel role for Mef2c/d in coordinating the transcriptional network that promotes early B-cell development.

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          Author and article information

          Journal
          Blood
          Blood
          American Society of Hematology
          1528-0020
          0006-4971
          Feb 04 2016
          : 127
          : 5
          Affiliations
          [1 ] Retroviral Pathogenesis and.
          [2 ] Virus Genomics, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.
          [3 ] Virus Genomics, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
          [4 ] Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, Erlangen, Germany.
          Article
          blood-2015-04-643270
          10.1182/blood-2015-04-643270
          26660426
          c3ddcd4f-1837-497a-8543-88af24d8d937
          History

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