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

Autor/innen

  • 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

Quellenangabe

  • Genes Dev 33: 23-24

Zusammenfassung

  • 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.


DOI

doi:10.1101/gad.330134.119