title: The mirn23a microRNA cluster antagonizes B cell development.
abstract: Ablation of microRNA synthesis by deletion of the microRNA-processing enzyme Dicer has demonstrated that microRNAs are necessary for normal hematopoietic differentiation and function. However, it is still unclear which specific microRNAs are required for hematopoiesis and at what developmental stages they are necessary. This is especially true for immune cell development. We previously observed that overexpression of the products of the mirn23a gene (microRNA-23a, -24-2, and 27a) in hematopoietic progenitors increased myelopoiesis with a reciprocal decrease in B lymphopoiesis, both in vivo and in vitro. In this study, we generated a microRNA-23a, -24-2, and 27a germline knockout mouse to determine whether microRNA-23a, -24-2, and 27a expression was essential for immune cell development. Characterization of hematopoiesis in microRNA-23a, -24-2, and 27a-/-mice revealed a significant increase in B lymphocytes in both the bone marrow and the spleen, with a concomitant decrease in myeloid cells (monocytes/granulocytes). Analysis of the bone marrow progenitor populations revealed a significant increase in common lymphoid progenitors and a significant decrease in both bone marrow common myeloid progenitors and granulocyte monocyte progenitors. Gene-expression analysis of primary hematopoietic progenitors and multipotent erythroid myeloid lymphoid cells showed that microRNA-23a, -24-2, and 27a regulates essential B cell gene-expression networks. Overexpression of microRNA-24-2 target Tribbles homolog 3 can recapitulate the microRNA-23a, -24-2, and 27a-/-phenotype in vitro, suggesting that increased B cell development in microRNA-23a, -24-2, and 27a null mice can be partially explained by a Tribbles homolog 3-dependent mechanism. Data from microRNA-23a, -24-2, and 27a-/-mice support a critical role for this microRNA cluster in regulating immune cell populations through repression of B lymphopoiesis.
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kurkewich
authors.affiliation: Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, Indiana, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bikorimana
authors.affiliation: Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, Indiana, USA.
authors.forename: Tan
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, Indiana, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Klopfenstein
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, Indiana, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Hallas
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA; Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, USA; and.
authors.forename: Gwen
authors.initials: G
authors.lastname: Stayback
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA; Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, USA; and.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: McDowell
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, Indiana, USA richdahl@iupui.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Dahl
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D001402:B-Lymphocytes / Q000473:pathology*; D001854:Bone Marrow Cells / Q000473:pathology; D018797:Cell Cycle Proteins / Q000502:physiology; D002460:Cell Line; D053263:Gene Regulatory Networks; D007074:Immunoglobulin G / Q000096:biosynthesis; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D022423:Myeloid Cells / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D018797:Cell Cycle Proteins; D007074:Immunoglobulin G; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; C474830:TRB3 protein, mouse
keywords: Trib3; hematopoiesis; lymphopoiesis; myelopoiesis