MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

Author:

Berenguer Jordi1,Herrera Antonio1,Vuolo Laura1,Torroba Blanca1,Llorens Franc23,Sumoy Lauro345,Pons Sebastian1

Affiliation:

1. Department of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona, IIBB-CSIC-IDIBAPS, Barcelona, Spain

2. Molecular and Cellular Neurobiotechnology Group, Institut de Bioenginyeria de Catalunya (IBEC), Parc Científic de Barcelona, Barcelona, Spain

3. Networked Biomedical Research Center for Neurodegenerative Diseases (CIBERNED), Madrid, Spain

4. Bioinformatics and Genomics Program, Center for Genomic Regulation (CRG)-Universitat Pompeu Fabra (UPF), Barcelona, Spain

5. Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Spain

Abstract

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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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