ADAR1 is vital for B cell lineage development in the mouse bone marrow.

Victoria Marcu-Malina,Gideon Rechavi,Ninette Amariglio,Itamar Goldstein,Sanja Goldberg,Einav Vax

doi:10.18632/oncotarget.11029

Victoria Marcu-Malina, Gideon Rechavi + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.11029

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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.

Highlights

RNA molecules undergo elaborate posttranscriptional modification, such as editing and methylation, collectively termed epitranscriptomics [1,2,3]
ADAR1 is required for the early stages of fetal and adult hematopoiesis [10, 25]
We asked whether ADAR1 is vital for the late phases of adult B lymphopoiesis, using a model system of Cd19-Creki-mediated recombination of floxed Adar

Summary

INTRODUCTION

RNA molecules undergo elaborate posttranscriptional modification, such as editing and methylation, collectively termed epitranscriptomics [1,2,3]. The majority of editing within UTRs is promiscuous, occurring within long intramolecular RNA duplexes formed by complementary pairing of inverted repeats: e.g., Alu retrotransposons in the human and orthologous short interspersed repetitive elements (SINE) in the mouse [1, 6]. Genetic ablation of Adar in the mouse is embryonic lethal at midgestation due to defective hematopoiesis and a detrimental type-I interferons response [8,9,10,11,12]. Recent studies in mouse models show that deletion of genes involved in the innate immune response to double-stranded (ds)RNA rescues ADAR1 deficient mice to birth [8, 17, 18]. In this study, using in vivo Cd19-Cre-mediated conditional ablation of Adar gene, we asked how ADAR1 deficiency affects the late stages of B lymphopoiesis predominantly in the BM

RESULTS AND DISCUSSION

MATERIALS AND METHODS

CONFLICTS OF INTEREST