title: ADAR1 is vital for B cell lineage development in the mouse bone marrow.
abstract: Adenosine deaminase acting on RNA (ADAR) 1 is the master editor of the transcriptome, catalyzing the conversion of adenosine to inosine (A-to-I). RNA transcripts fold into a variety of secondary structures including long intramolecular RNA duplexes that are the major substrate of ADAR1. Most A-to-I editing sites occur within RNA duplexes formed by complementary pairing of inverted retrotransposable elements interspersed within noncoding regions of transcripts. This catalytic activity of ADAR1 most likely prevents the abnormal activation of cytosolic nucleic acid sensors by self-dsRNAs. Homozygous disruption of mouse Adar is embryonic lethal due to a toxic type-I interferons response and correspondingly biallelic missense mutations in human ADAR1 cause a severe congenital interferonopathy. Here, we report that Cd19-Cre-mediated Adar gene ablation in the mouse causes a significant defect in the final stages of B cell development with an almost complete absence of newly formed immature and CD23+ mature recirculating B cells in the BM. Adar ablation in pre-B cells induced upregulation of typical interferon-stimulated genes (ISGs) and apoptosis upon further maturation. ADAR1 deficiency also inhibited the in vitro, IL-7-mediated, differentiation of BM-derived B cell precursors. In summary, ADAR1 is required, non-redundantly, for normal B lymphopoiesis in the BM and peripheral maintenance.
authors: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.
authors: Victoria
authors: V
authors: Marcu-Malina
authors: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.
authors: Sanja
authors: S
authors: Goldberg
authors: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.
authors: Einav
authors: E
authors: Vax
authors: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.|The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
authors: Ninette
authors: N
authors: Amariglio
authors: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.|Rheumatic Diseases Unit, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Itamar
authors: I
authors: Goldstein
authors: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.|Department of Pediatric Hemato-Oncology, Chaim Sheba Academic Medical Center, Tel Hashomer, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Gideon
authors: G
authors: Rechavi
mesh_terms: D000243:Adenosine Deaminase / Q000502:physiology*; D000818:Animals; D018941:Antigens, CD19 / Q000502:physiology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D001853:Bone Marrow / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D015851:Interleukin-7 / Q000502:physiology; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018941:Antigens, CD19; C000604812:CD19 antigen, mouse; D015851:Interleukin-7; C000599465:ADAR1 protein, mouse; D000243:Adenosine Deaminase
keywords: ADAR1; B cell; Immune response; Immunity; Immunology and Microbiology Section; RNA editing; epitranscriptomics; lymphopoiesis