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  • The EMBO Journal (2008) 27, 2616 - 2627
  • doi:10.1038/emboj.2008.172

Published online: 28 August 2008

Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells

Elisabetta Ferretti1,a, Enrico De Smaele1,a, Evelina Miele1, Pietro Laneve2, Agnese Po1, Marianna Pelloni1, Arianna Paganelli1, Lucia Di Marcotullio1, Elisa Caffarelli2, Isabella Screpanti1,3, Irene Bozzoni2,3,4 and Alberto Gulino1,3,5

  1. Department of Experimental Medicine, Sapienza University, Roma, Italy
  2. Institute of Molecular Biology and Pathology, Consiglio Nazionale delle Ricerche, Sapienza University, Roma, Italy
  3. Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University, Roma, Italy
  4. Department of Genetics and Molecular Biology, Sapienza University, Roma, Italy
  5. Neuromed Institute, Pozzilli, Italy

Correspondence to:

Alberto Gulino, Department of Experimental Medicine, Sapienza University, 324 viale Regina Elena, 00161 Roma, Italy. Tel.: +39 6 4464021; Fax: +39 6 4461974; E-mail: alberto.gulino@uniroma1.it

aThese authors contributed equally to this work

Received 4 June 2008; Accepted 6 August 2008

MicroRNAs (miRNA) are crucial post-transcriptional regulators of gene expression and control cell differentiation and proliferation. However, little is known about their targeting of specific developmental pathways. Hedgehog (Hh) signalling controls cerebellar granule cell progenitor development and a subversion of this pathway leads to neoplastic transformation into medulloblastoma (MB). Using a miRNA high-throughput profile screening, we identify here a downregulated miRNA signature in human MBs with high Hh signalling. Specifically, we identify miR-125b and miR-326 as suppressors of the pathway activator Smoothened together with miR-324-5p, which also targets the downstream transcription factor Gli1. Downregulation of these miRNAs allows high levels of Hh-dependent gene expression leading to tumour cell proliferation. Interestingly, the downregulation of miR-324-5p is genetically determined by MB-associated deletion of chromosome 17p. We also report that whereas miRNA expression is downregulated in cerebellar neuronal progenitors, it increases alongside differentiation, thereby allowing cell maturation and growth inhibition. These findings identify a novel regulatory circuitry of the Hh signalling and suggest that misregulation of specific miRNAs, leading to its aberrant activation, sustain cancer development.

  • Keywords:

    • cancer,
    • expression profiling,
    • Hedgehog,
    • microRNA,
    • post-transcriptional control