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ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling

Nature Immunology volume 10, pages 109–115 (2009)Cite this article

A Corrigendum to this article was published on 01 May 2009

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Abstract

The deaminase ADAR1 edits adenosines in nuclear transcripts of nervous tissue and is required in the fetal liver of the developing mouse embryo. Here we show by inducible gene disruption in mice that ADAR1 is essential for maintenance of both fetal and adult hematopoietic stem cells. Loss of ADAR1 in hematopoietic stem cells led to global upregulation of type I and II interferon–inducible transcripts and rapid apoptosis. Our findings identify ADAR1 as an essential regulator of hematopoietic stem cell maintenance and suppressor of interferon signaling that may protect organisms from the deleterious effects of interferon activation associated with many pathological processes, including chronic inflammation, autoimmune disorders and cancer.

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Figure 1: ADAR1 is dispensable for the emergence of phenotypic HSCs and multipotent progenitors in the fetal liver.
Figure 2: Near-complete loss of fetal liver contribution to adult bone marrow hematopoiesis after induced ADAR1 deficiency.
Figure 3: Induced deletion of Adar in HSCs of adult mice leads to hyperproliferation and apoptosis.
Figure 4: ADAR1 deficiency in HSCs leads to a global upregulation of interferon-inducible transcripts.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

Change history

  • 09 April 2009

    In the version of this article initially published, the Cre-transgenic mouse is identified incorrectly as Tg(SV40-cre)1Jrg. The correct mouse strain should be Tg(SCL6E5-Cre)1Jrg, and the citation describing this mouse (ref. 29) should be as follows: Gothert, J.R. et al. In vivo fate-tracing studies using the Scl stem cell enhancer: embryonic hematopoietic stem cells significantly contribute to adult hematopoiesis. Blood 105, 2724–2732 (2005). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Higuchi and P.H. Seeburg (Max-Planck Institute for Medical Research) for Adar mutant mice; K. Rajewsky (Immune Disease Institute, Boston) for Mx1-Cre mice; J. Goethert (University Hospital Essen) for SCL-Cre-ERT mice; the Dana-Farber Cancer Institute and Children's Hospital animal facility staff for care of experimental mice; J. Daley and S. Lazo-Kallanian of the Dana-Farber Cancer Institute flow cytometry facility for assistance with cell sorting; J. Shea for technical assistance; T.R. Golub for support in gene expression analysis; and M. Higuchi, A. Athanasiadis, S. Maas and L. Purton for critical comments on the manuscript. Supported by the Leukemia and Lymphoma Society (C.R.W.) and the Howard Hughes Medical Institute (S.H.O.).

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Author notes

  1. Carl R Walkley

    Present address: Present address: St. Vincent's Institute of Medical Research, Princes Street, Fitzroy, Victoria 3065, Australia.,

Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute; Harvard Medical School,

    Jochen C Hartner, Carl R Walkley, Jun Lu & Stuart H Orkin

  2. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Jochen C Hartner, Carl R Walkley, Jun Lu & Stuart H Orkin

  3. Division of Hematology-Oncology, Children's Hospital Boston, Boston, 02115, Massachusetts, USA

    Jochen C Hartner, Carl R Walkley & Stuart H Orkin

  4. Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, USA

    Jun Lu

  5. Howard Hughes Medical Institute, Boston, 02115, Massachusetts, USA

    Stuart H Orkin

  6. Harvard Stem Cell Institute, Boston, 02115, Massachusetts, USA

    Stuart H Orkin

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Contributions

J.C.H. conceived the study, designed and did experiments, analyzed and interpreted data and wrote the paper; C.R.W. did experiments and analyzed and interpreted data; J.L. analyzed and interpreted data; and S.H.O. analyzed and interpreted data and wrote the paper.

Corresponding author

Correspondence to Stuart H Orkin.

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Hartner, J., Walkley, C., Lu, J. et al. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol 10, 109–115 (2009). https://doi.org/10.1038/ni.1680

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