Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters

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. H...

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Bibliographic Details
Published in:Cell 2008-03, Vol.132 (5), p.875
Main Authors: Ventura, Andrea, Young, Amanda G, Winslow, Monte M, Lintault, Laura, Meissner, Alex, Erkeland, Stefan J, Newman, Jamie, Bronson, Roderick T, Crowley, Denise, Stone, James R, Jaenisch, Rudolf, Sharp, Phillip A, Jacks, Tyler
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:1097-4172
DOI:10.1016/j.cell.2008.02.019