title: MicroRNA 22 regulates cell cycle length in cerebellar granular neuron precursors.
abstract: During cerebellum development, Sonic hedgehog (Shh)-induced proliferation of cerebellar granular neuronal precursors (CGNPs) is potently inhibited by bone morphogenetic proteins (BMPs). We have previously reported the upregulation of TIEG-1 and Mash1, two antimitotic factors that modulate MYCN transcription and N-Myc activity, in response to BMP2. To gain further insight into the BMP antimitotic mechanism, we used microRNA (miRNA) arrays to compare the miRNAs of CGNPs proliferating in response to Shh with those of CGNPs treated with Shh plus BMP2. The array analysis revealed that miRNA 11 (miR-22) levels significantly increased in cells treated with BMP2. Additionally, in P7 mouse cerebellum, miR-22 distribution mostly recapitulated the combination of BMP2 and BMP4 expression patterns. Accordingly, in CGNP cultures, miR-22 overexpression significantly reduced cell proliferation, whereas miR-22 suppression diminished BMP2 antiproliferative activity. In contrast to BMP2, miR-22 did not induce neural differentiation but instead significantly increased cell cycle length. Consistent with the central role played by N-myc on CGNP proliferation, Max was revealed as a direct target of miR-22, and miR-22 expression caused a significant reduction of Max protein levels and N-myc/Max-dependent promoter activity. Therefore, we conclude that, in addition to the previously described mechanisms, miR-22 plays a specific role on downstream BMPs through cerebellum growth.
authors.affiliation: Department of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona, IIBB-CSIC-IDIBAPS, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Berenguer
authors.forename: Antonio
authors.initials: A
authors.lastname: Herrera
authors.forename: Laura
authors.initials: L
authors.lastname: Vuolo
authors.forename: Blanca
authors.initials: B
authors.lastname: Torroba
authors.forename: Franc
authors.initials: F
authors.lastname: Llorens
authors.forename: Lauro
authors.initials: L
authors.lastname: Sumoy
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pons
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019485:Bone Morphogenetic Proteins; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; D016271:Proto-Oncogene Proteins c-myc; C068422:Max protein, mouse