title: An allelic series of miR-17 ∼ 92-mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron.
abstract: Polycistronic microRNA (miRNA) clusters are a common feature of vertebrate genomes. The coordinated expression of miRNAs belonging to different seed families from a single transcriptional unit suggests functional cooperation, but this hypothesis has not been experimentally tested. Here we report the characterization of an allelic series of genetically engineered mice harboring selective targeted deletions of individual components of the miR-17 ∼ 92 cluster. Our results demonstrate the coexistence of functional cooperation and specialization among members of this cluster, identify a previously undescribed function for the miR-17 seed family in controlling axial patterning in vertebrates and show that loss of miR-19 selectively impairs Myc-driven tumorigenesis in two models of human cancer. By integrating phenotypic analysis and gene expression profiling, we provide a genome-wide view of how the components of a polycistronic miRNA cluster affect gene expression in vivo. The reagents and data sets reported here will accelerate exploration of the complex biological functions of this important miRNA cluster.
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Oncology Research Unit, Pfizer, Inc., Pearl River, New York, USA.
authors.forename: Yoon-Chi
authors.initials: YC
authors.lastname: Han
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Joana A
authors.identifier: 0000000327656985
authors.initials: JA
authors.lastname: Vidigal
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, New York, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Mu
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, New York, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Yao
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Irtisha
authors.initials: I
authors.lastname: Singh
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: González
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, New York, USA.
authors.forename: Carla P
authors.initials: CP
authors.lastname: Concepcion
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ciro
authors.initials: C
authors.lastname: Bonetti
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ogrodowski
authors.affiliation: 1] Human Oncology and Pathogenesis Program. Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Carver
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.affiliation: 1] Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. [2] Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Doron
authors.initials: D
authors.lastname: Betel
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Leslie
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ventura
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology; D063646:Carcinogenesis / Q000235:genetics; D002478:Cells, Cultured; D005143:Eyelids / Q000002:abnormalities; D005787:Gene Frequency; D005804:Genes, Lethal; D055106:Genome-Wide Association Study; D008607:Intellectual Disability / Q000235:genetics; D017880:Limb Deformities, Congenital / Q000235:genetics; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics; D005810:Multigene Family; D009154:Mutation; D014138:Tracheoesophageal Fistula / Q000235:genetics
chemical_list: C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs