title: Role of the miR-17∼92 cluster family in cerebellar and medulloblastoma development.
abstract: The miR-17∼92 cluster family is composed of three members encoding microRNAs that share seed sequences. To assess their role in cerebellar and medulloblastoma (MB) development, we deleted the miR-17∼92 cluster family in Nestin-positive neural progenitors and in mice heterozygous for the Sonic Hedgehog (SHH) receptor Patched 1 (Ptch1(+/-)). We show that mice in which we conditionally deleted the miR-17∼92 cluster (miR-17∼92(floxed/floxed); Nestin-Cre(+)) alone or together with the complete loss of the miR-106b∼25 cluster (miR-106b∼25(-/-)) were born alive but with small brains and reduced cerebellar foliation. Remarkably, deletion of the miR-17∼92 cluster abolished the development of SHH-MB in Ptch1(+/-) mice. Using an orthotopic transplant approach, we showed that granule neuron precursors (GNPs) purified from the cerebella of postnatal day 7 (P7) Ptch1(+/-); miR-106b∼25(-/-) mice and overexpressing Mycn induced MBs in the cortices of naïve recipient mice. In contrast, GNPs purified from the cerebella of P7 Ptch1(+/-); miR-17∼92(floxed/floxed); Nestin-Cre(+) animals and overexpressing Mycn failed to induce tumors in recipient animals. Taken together, our findings demonstrate that the miR-17∼92 cluster is dispensable for cerebellar development, but required for SHH-MB development.
authors.affiliation: Department of Tumor Cell Biology, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Frederique
authors.initials: F
authors.lastname: Zindy
authors.affiliation: Department of Tumor Cell Biology, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA Present address: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kawauchi
authors.affiliation: Department of Genetics, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA Present address: Genomic Instability Research Center, Ajou University, School of Medicine, Suwon 443-749, South Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Tumor Cell Biology, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA Present address: Institut Curie/CNRS UMR 3306/INSERM U1005 - Building 110 - Centre Universitaire, 91405 Orsay, Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Ayrault
authors.affiliation: Department of Tumor Cell Biology, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Ben Merzoug
authors.affiliation: Department of Genetics, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ventura
authors.affiliation: Department of Tumor Cell Biology, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA martine.roussel@stjude.org.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
keywords: Cerebellum; Development; Granule neuron progenitors (GNPs); Medulloblastoma; MicroRNA; Nestin; miR-17∼92 and miR-106b∼25 clusters