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SMAD proteins control DROSHA-mediated microRNA maturation

Nature volume 454, pages 56–61 (2008)Cite this article

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Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-β and BMPs is mediated by miR-21. miR-21 downregulates PDCD4 (programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-β and BMP signalling promotes a rapid increase in expression of mature miR-21 through a post-transcriptional step, promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR-21 (pre-miR-21) by the DROSHA (also known as RNASEN) complex. TGF-β- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-β and BMP signalling pathways.

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Figure 1: miR-21 is critical for the modulation of the VSMC phenotype by BMP.
Figure 2: Post-transcriptional regulation of miR-21 biosynthesis by TGF-β.
Figure 3: Interaction of SMADs with p68, a component of the DROSHA complex.
Figure 4: Association of SMADs with pri-miRNA promotes processing by DROSHA.
Figure 5: SMAD4-independent mechanism of maturation of pri-miRNA.

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Change history

  • 21 July 2008

    In the online-only extended Methods, the miR-214 primer sequence was corrected on 21st July 2008

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Acknowledgements

We thank M.-C. Chan and N. Neuman for critical discussion and H. Surks and M. Ivan for critical reading of the manuscript and technical advice. We also thank S. Kato, E. Olson, R. Bassel-Duby, Y.Y. Mo, K. Miyazono, B. Cochran and G.-R. Wang for sharing reagents. This work was supported by grants from the National Institute of Health HD042149 and HL082854 to A.H. and HL086572 to G.L.

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Authors and Affiliations

  1. Department of Biochemistry, Tufts University School of Medicine,

    Brandi N. Davis & Akiko Hata

  2. Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA ,

    Brandi N. Davis, Aaron C. Hilyard, Giorgio Lagna & Akiko Hata

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Correspondence to Akiko Hata.

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Davis, B., Hilyard, A., Lagna, G. et al. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56–61 (2008). https://doi.org/10.1038/nature07086

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