title: Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins.
abstract: The Mef2 family transcriptional regulator Mef2c (myocyte enhancer factor 2c) is highly expressed in maturing bone marrow and peripheral mature B-cells. To evaluate the role of this transcription factor in B-cell development, we generated a B-cell-specific conditional deletion of Mef2c using the Mb-1-Cre transgene that is expressed during the early stages of immunoglobulin rearrangement. Young mice possessing this defect demonstrated a significant impairment in B-cell numbers in bone marrow and spleen. This phenotype was evident in all B-cell subsets; however, as the animals mature, the deficit in the peripheral mature B-cell compartments was overcome. The absence of Mef2c in mature B-cells led to unique CD23+ and CD23- subsets that were evident in Mef2c knockout primary samples as well as Mef2c-deficient cultured, differentiated B-cells. Genome-wide expression analysis of immature and mature B-cells lacking Mef2c indicated altered expression for a number of key regulatory proteins for B-cell function including Ciita, CD23, Cr1/Cr2 and Tnfsf4. Chromatin immunoprecipitation analysis confirmed Mef2c binding to the promoters of these genes indicating a direct link between the presence (or absence) of Mef2c and altered transcriptional control in mature B-cells.
authors.affiliation: The Division of Microbiology and Immunology,  Department of Pathology,  University of Utah School of Medicine, Salt Lake City, UT 84112,  USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Debnath
authors.forename: Kirstin M
authors.initials: KM
authors.lastname: Roundy
authors.forename: Peter D
authors.initials: PD
authors.lastname: Pioli
authors.forename: Janis J
authors.initials: JJ
authors.lastname: Weis
authors.forename: John H
authors.initials: JH
authors.lastname: Weis
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D064326:MEF2 Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D015534:Trans-Activators