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

• Published in: Genes & development Vol. 33; no. 23-24; pp. 1673 - 1687
• Main Authors: Labi, Verena, Peng, Siying, Klironomos, Filippos, Munschauer, Mathias, Kastelic, Nicolai, Chakraborty, Tirtha, Schoeler, Katia, Derudder, Emmanuel, Martella, Manuela, Mastrobuoni, Guido, Hernandez-Miranda, Luis R, Lahmann, Ines, Kocks, Christine, Birchmeier, Carmen, Kempa, Stefan, Quintanilla-Martinez de Fend, Leticia, Landthaler, Markus, Rajewsky, Nikolaus, Rajewsky, Klaus
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.12.2019
• Subjects: 3' Untranslated Regions - genetics; Animals; B-Lymphocytes - cytology; B-Lymphocytes - pathology; Bcl-2-Like Protein 11 - genetics; Bcl-2-Like Protein 11 - metabolism; Cell Survival - genetics; Gene Expression Regulation, Developmental - genetics; Gene Knockout Techniques; Hematopoiesis - genetics; Lung - embryology; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Mutation; Research Paper; Stress, Physiological; apoptosis; B cells; miR-17∼92; seed match mutation; lung development; BIM
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.330134.119

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 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 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.