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

EMBO J. 2008 Oct 8;27(19):2616-27. doi: 10.1038/emboj.2008.172. Epub 2008 Aug 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Base Sequence
  • Cell Differentiation
  • Cell Proliferation
  • Cerebellum / cytology*
  • Chromosomes, Human, Pair 17 / genetics
  • Gene Expression Profiling
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism*
  • Medulloblastoma / pathology
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microarray Analysis
  • Middle Aged
  • Molecular Sequence Data
  • Neurons / cytology
  • Neurons / physiology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / physiology*
  • Smoothened Receptor
  • Stem Cells / cytology
  • Stem Cells / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zinc Finger Protein GLI1


  • GLI1 protein, human
  • Hedgehog Proteins
  • MIRN125 microRNA, human
  • MicroRNAs
  • Receptors, G-Protein-Coupled
  • SMO protein, human
  • Smoothened Receptor
  • Transcription Factors
  • Zinc Finger Protein GLI1