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Control of oligodendroglial cell number by the miR-17~92 family of miRNA cluster (miRNA Exiqon Part)

ABSTRACT: The generation of myelinating cells in the central nervous system (CNS) requires the initiation of specific gene-expression programs in oligodendrocytes. We reasoned that miRNAs could play an important role in this process by regulating critical developmental genes. Microarray profiling of cultured oligodendrocytes identifies the miR-17~92 family of miRNA cluster as highly enriched miRNAs in oligodendrocytes.We specifically deleted the miR-17~92 cluster in oligodendrocytes using the 2´3´-cyclic nucleotide 3´-phosphodiesterase (CNP)-Cre mice. Absence of miR-17~92 leads to a reduction of oligodendrocyte number in vivo and we find that the expression of these miRNAs in primary cultures of oligodendrocytes promotes cell proliferation by influencing Akt signalling. Together, these results suggest that the miRNA pathway is essential in determining oligodendroglial cell number and that the miR-17~92 cluster is crucial in this process.

ORGANISM(S): Human alphaherpesvirus 1 Betapolyomavirus hominis Mus musculus Rattus norvegicus Human gammaherpesvirus 8 JC polyomavirus Betapolyomavirus macacae Homo sapiens Human immunodeficiency virus 1 human gammaherpesvirus 4 Human betaherpesvirus 5

PROVIDER: GSE21799 | GEO | 2010/06/01

SECONDARY ACCESSION(S): PRJNA129343

REPOSITORIES: GEO

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Project description:Medulloblastomas (MBs) are the most common brain tumors in children. Some are thought to originate from cerebellar granule neuron progenitors (GNPs) that fail to undergo normal cell cycle exit and differentiation. Since microRNAs regulate numerous aspects of cellular physiology and development, we reasoned that alterations in miRNA expression might contribute to MB. We tested this hypothesis using two spontaneous mouse MB models with specific initiating mutations, Ink4c-/-; Ptch1+/- and Ink4c-/-; p53-/-. We found that 26 miRNAs showed increased expression and 24 miRNAs showed decreased expression in proliferating mouse GNPs and MBs relative to mature mouse cerebellum, regardless of genotype. Among the 26 overexpressed miRNAs, nine were encoded by the miR-17~92 cluster family, a group of microRNAs implicated as oncogenes in several tumor types. Analysis of human MBs demonstrated that three miR-17~92 cluster miRNAs (miR-92, miR-19a and miR-20) were also overexpressed in human MBs with a constitutively activated SHH signaling pathway, but not in other forms of the disease. To test whether the miR-17~92 cluster could promote MB formation, we enforced expression of these miRNAs in GNPs isolated from cerebella of postnatal (P) day P6 Ink4c-/-; Ptch1+/- mice. These, but not similarly engineered cells from Ink4c-/-; p53-/- mice, formed MBs in orthotopic transplants with complete penetrance. Interestingly, orthotopic mouse tumors ectopically expressing miR-17~92 lost expression of the wild-type Ptch1 allele. Our findings suggest a functional collaboration between the miR-17~92 cluster and the SHH signaling pathway in the development of MBs in mouse and man. Samples: purified CGNP-like mouse medulloblastoma cells; purified CGNPs from age day 6 (P6) mice; whole cerebellum from P6 mice; whole cerebellum from 1 month old mice. Each from three backgrounds (except tumors) - wt; Ptc+/-,Ink4c-/-; p53-/-,Ink4c-/-. Two to five biological replicates each.

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Control of oligodendroglial cell number by the miR-17~92 family of miRNA cluster (miRNA Exiqon Part)

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