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

miR-17 similar to 92, miR-106b similar to 25, and miR-106a similar to 363 belong to a family of highly conserved miRNA clusters. Amplification and overexpression of miR-17 similar to 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 miR17 similar to 92 die shortly after birth with lung hypoplasia and a ventricular septal defect. The miR-17 similar to 92 cluster is also essential for B cell development. Absence of miR-17 similar to 92 leads to increased levels of the proapoptotic protein Bim and inhibits B cell development at the pro-Bto pre-B transition. Furthermore, while ablation of miR-106b similar to 25 or miR-106a similar to 363 has no obvious phenotypic consequences, compound mutant embryos lacking both miR-106b similar to 25 and miR-17 similar to 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 similar to 92 and its functions during B lymphopoiesis and lung development.