Targeted Deletion Reveals Essential and Overlapping Functions of the miR-17 Through 92 Family of miRNA Clusters

Cell. 2008 Mar 7;132(5):875-86. doi: 10.1016/j.cell.2008.02.019.

Abstract

miR-17 approximately 92, miR-106b approximately 25, and miR-106a approximately 363 belong to a family of highly conserved miRNA clusters. Amplification and overexpression of miR-1792 is observed in human cancers, and its oncogenic properties have been confirmed in a mouse model of B cell lymphoma. Here we show that mice deficient for miR-17 approximately 92 die shortly after birth with lung hypoplasia and a ventricular septal defect. The miR-17 approximately 92 cluster is also essential for B cell development. Absence of miR-17 approximately 92 leads to increased levels of the proapoptotic protein Bim and inhibits B cell development at the pro-B to pre-B transition. Furthermore, while ablation of miR-106b approximately 25 or miR-106a approximately 363 has no obvious phenotypic consequences, compound mutant embryos lacking both miR-106b approximately 25 and miR-17 approximately 92 die at midgestation. These results provide key insights into the physiologic functions of this family of microRNAs and suggest a link between the oncogenic properties of miR-17 approximately 92 and its functions during B lymphopoiesis and lung development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • B-Lymphocytes / cytology
  • Bcl-2-Like Protein 11
  • Cell Survival
  • Embryonic Stem Cells / metabolism
  • Fetus / cytology
  • Genes, Lethal
  • Heart Septal Defects, Ventricular / genetics
  • Lung Diseases / genetics
  • Membrane Proteins / metabolism
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Multigene Family*
  • Proto-Oncogene Proteins / metabolism
  • Sequence Deletion*

Substances

  • 3' Untranslated Regions
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Membrane Proteins
  • MicroRNAs
  • Proto-Oncogene Proteins