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Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells
Author(s) -
Ferretti Elisabetta,
De Smaele Enrico,
Miele Evelina,
Laneve Pietro,
Po Agnese,
Pelloni Marianna,
Paganelli Arianna,
Di Marcotullio Lucia,
Caffarelli Elisa,
Screpanti Isabella,
Bozzoni Irene,
Gulino Alberto
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.172
Subject(s) - biology , smoothened , microrna , gli1 , hedgehog , hedgehog signaling pathway , microbiology and biotechnology , progenitor cell , downregulation and upregulation , cellular differentiation , transcription factor , regulation of gene expression , cell growth , stem cell , signal transduction , genetics , gene
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.