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

Andrea Ventura, Amanda G. Young, Monte M. Winslow, Laura Lintault, Alex Meissner, Stefan J. Erkeland, Jamie Newman, Roderick T. Bronson, Denise Crowley, James R. Stone, Rudolf Jaenisch, Phillip A. Sharp, Tyler Jacks

Research output: Contribution to journalArticlepeer-review

1427 Scopus citations

Abstract

miR-17∼92, miR-106b∼25, and miR-106a∼363 belong to a family of highly conserved miRNA clusters. Amplification and overexpression of miR-17∼92 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∼92 die shortly after birth with lung hypoplasia and a ventricular septal defect. The miR-17∼92 cluster is also essential for B cell development. Absence of miR-17∼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∼25 or miR-106a∼363 has no obvious phenotypic consequences, compound mutant embryos lacking both miR-106b∼25 and miR-17∼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∼92 and its functions during B lymphopoiesis and lung development.

Original languageEnglish
Pages (from-to)875-886
Number of pages12
JournalCell
Volume132
Issue number5
DOIs
StatePublished - 7 Mar 2008
Externally publishedYes

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