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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.
ACKNOWLEDGMENTS
We are deeply grateful to Deborah Burks for editing the manuscript, to Anghara Menendez for invaluable research assistance, and to all researchers who sent us the cDNAs as detailed in Materials and Methods. Monoclonal antibodies obtained from the Developmental Studies Hybridoma Bank were developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA.
Work in S.P.'s laboratory is supported by the Spanish Ministry of Education grants BFU2008-02424/BFI and BFU2011-24099.