title: Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, Sapienza University, Roma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Evelina
authors.initials: E
authors.lastname: Miele
authors.forename: Pietro
authors.initials: P
authors.lastname: Laneve
authors.forename: Agnese
authors.initials: A
authors.lastname: Po
authors.forename: Marianna
authors.initials: M
authors.lastname: Pelloni
authors.forename: Arianna
authors.initials: A
authors.lastname: Paganelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Elisa
authors.initials: E
authors.lastname: Caffarelli
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino