Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat

  1. Klaus Rajewsky1,2
  1. 1Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin-Buch 13125, Germany;
  2. 2Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
  3. 3Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria;
  4. 4Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin-Buch 13125, Germany;
  5. 5Institute for Biomedical Ageing Research, University of Innsbruck, Innsbruck 6020, Austria;
  6. 6Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, Tübingen 72076, Germany
  1. Corresponding authors: verena.labi{at}i-med.ac.at, klaus.rajewsky{at}mdc-berlin.de
  • Present addresses: 7Beijing IDMO Company Limited, Beijing 100000, China; 8Department of Pediatrics, Charité – University Hospital Berlin, Berlin 13353, Germany; 9Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; 10CRISPR Therapeutics, Cambridge, MA 02139, USA.

Abstract

Knockout of the ubiquitously expressed miRNA-17∼92 cluster in mice produces a lethal developmental lung defect, skeletal abnormalities, and blocked B lymphopoiesis. A shared target of miR-17∼92 miRNAs is the pro-apoptotic protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17∼92:Bim interactions to the complex miR-17∼92 knockout phenotype, we used a system of conditional mutagenesis of the nine Bim 3′ UTR miR-17∼92 seed matches. Blocking miR-17∼92:Bim interactions early in development phenocopied the lethal lung phenotype of miR-17∼92 ablation and generated a skeletal kinky tail. In the hematopoietic system, instead of causing the predicted B cell developmental block, it produced a selective inability of B cells to resist cellular stress; and prevented B and T cell hyperplasia caused by Bim haploinsufficiency. Thus, the interaction of miR-17∼92 with a single target is essential for life, and BIM regulation by miRNAs serves as a rheostat controlling cell survival in specific physiological contexts.

Keywords

Footnotes

  • Received June 27, 2019.
  • Accepted October 2, 2019.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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  1. Genes & Dev. 33: 1673-1687 © 2019 Labi et al.; Published by Cold Spring Harbor Laboratory Press

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