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. 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.
Ventura
Andrea
A
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Young
Amanda G
AG
Winslow
Monte M
MM
Lintault
Laura
L
Meissner
Alex
A
Erkeland
Stefan J
SJ
Newman
Jamie
J
Bronson
Roderick T
RT
Crowley
Denise
D
Stone
James R
JR
Jaenisch
Rudolf
R
Sharp
Phillip A
PA
Jacks
Tyler
T
D020413:3' Untranslated Regions / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D053595:Embryonic Stem Cells / Q000378:metabolism; D005333:Fetus / Q000166:cytology; D005804:Genes, Lethal; D006345:Heart Septal Defects, Ventricular / Q000235:genetics; D008171:Lung Diseases / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D005810:Multigene Family; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017384:Sequence Deletion
D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins