Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat
- Verena Labi1,2,3,
- Siying Peng2,7,
- Filippos Klironomos1,4,8,
- Mathias Munschauer1,4,9,
- Nicolai Kastelic1,4,
- Tirtha Chakraborty2,10,
- Katia Schoeler3,
- Emmanuel Derudder1,2,5,
- Manuela Martella6,
- Guido Mastrobuoni1,4,
- Luis R. Hernandez-Miranda1,
- Ines Lahmann1,
- Christine Kocks1,4,
- Carmen Birchmeier1,
- Stefan Kempa1,4,
- Leticia Quintanilla-Martinez de Fend6,
- Markus Landthaler1,4,
- Nikolaus Rajewsky1,4 and
- Klaus Rajewsky1,2
- 1Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin-Buch 13125, Germany;
- 2Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria;
- 4Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin-Buch 13125, Germany;
- 5Institute for Biomedical Ageing Research, University of Innsbruck, Innsbruck 6020, Austria;
- 6Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, Tübingen 72076, Germany
- Corresponding authors: verena.labi{at}i-med.ac.at, klaus.rajewsky{at}mdc-berlin.de
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.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.330134.119.
- Received June 27, 2019.
- Accepted October 2, 2019.
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