title: Essential control of early B-cell development by Mef2 transcription factors.
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.
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Julia
authors.initials: J
authors.lastname: Herglotz
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Unrau
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Friderike
authors.initials: F
authors.lastname: Hauschildt
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Meike
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Neele
authors.initials: N
authors.lastname: Kriebitzsch
authors.affiliation: Virus Genomics, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Virus Genomics, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Indenbirken
authors.affiliation: Virus Genomics, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Spohn
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Marion
authors.initials: M
authors.lastname: Ziegler
authors.affiliation: Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuh
authors.affiliation: Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Jäck
authors.affiliation: Retroviral Pathogenesis and.
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D010766:Phosphorylation; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; C578044:Mef2d protein, mouse; D048054:Mitogen-Activated Protein Kinase 7