Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat
Authors
- V. Labi
- S. Peng
- F. Klironomos
- M. Munschauer
- N. Kastelic
- T. Chakraborty
- K. Schoeler
- E. Derudder
- M. Martella
- G. Mastrobuoni
- L.R. Hernandez-Miranda
- I. Lahmann
- C. Kocks
- C. Birchmeier
- S. Kempa
- L. Quintanilla-Martinez de Fend
- M. Landthaler
- N. Rajewsky
- K. Rajewsky
Journal
- Genes & Development
Citation
- Genes Dev 33: 23-24
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.