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The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation

Abstract

Understanding the molecular mechanisms that regulate cellular proliferation and differentiation is a central theme of developmental biology. MicroRNAs (miRNAs) are a class of regulatory RNAs of 22 nucleotides that post-transcriptionally regulate gene expression1,2. Increasing evidence points to the potential role of miRNAs in various biological processes3,4,5,6,7,8. Here we show that miRNA-1 (miR-1) and miRNA-133 (miR-133), which are clustered on the same chromosomal loci, are transcribed together in a tissue-specific manner during development. miR-1 and miR-133 have distinct roles in modulating skeletal muscle proliferation and differentiation in cultured myoblasts in vitro and in Xenopus laevis embryos in vivo. miR-1 promotes myogenesis by targeting histone deacetylase 4 (HDAC4), a transcriptional repressor of muscle gene expression. By contrast, miR-133 enhances myoblast proliferation by repressing serum response factor (SRF). Our results show that two mature miRNAs, derived from the same miRNA polycistron and transcribed together, can carry out distinct biological functions. Together, our studies suggest a molecular mechanism in which miRNAs participate in transcriptional circuits that control skeletal muscle gene expression and embryonic development.

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Figure 1: Expression of miR-1 and miR-133 in cardiac and skeletal muscle during development.
Figure 2: Regulation of myoblast proliferation and differentiation by miR-1 and miR-133.
Figure 3: Control of cardiac and skeletal muscle development by miR-1 and miR-133 in vivo.
Figure 4: Identification of miR-1 and miR-133 target genes in skeletal muscle.
Figure 5: Model of miR-1 and miR-133-mediated regulation of skeletal muscle proliferation and differentiation.

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Acknowledgements

We thank members of our laboratories for discussion and support; T. McKinsey for advice on the HDAC4 antibodies; E. Amaya for the dsRed construct; S. Smyth use of electroporation apparatus; M. von Drehl for histology; M. Majesky and C. Patterson for discussion and critically reading the manuscript. E.M.M. is funded by a National Science Foundation graduate research fellowship. J.M.T. is a Frederick Gardner Cottrell Postdoctoral Fellow. S.M.H. is a General Motors Cancer Research Foundation Scholar. F.L.C. was supported by the US National Institutes of Health (NIH) and the American Heart Association. D.-Z.W. is a Basil O'Connor Scholar of the March of Dimes Birth Defects Foundation and was supported by the NIH, the Muscular Dystrophy Association and an American Heart Association Grant-in-Aid.

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Correspondence to Da-Zhi Wang.

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Supplementary information

Supplementary Fig. 1

miRNA array analysis of C2C12 cells. (PDF 692 kb)

Supplementary Fig. 2

Expression of miR-1, miR-133 and skeletal muscle differentiation marker genes in C2C12 cells. (PDF 1095 kb)

Supplementary Fig. 3

Expression of miR-1 and miR-133 in cardiac and skeletal muscle in adult mice and throughout development. (PDF 1290 kb)

Supplementary Fig. 4

Expression of miR-1 and miR-133 primary transcripts in cardiac and skeletal muscle. (PDF 145 kb)

Supplementary Fig. 5

A miR-1 and miR-133 enhancer directs reporter gene expression in cardiac and skeletal muscle. (PDF 219 kb)

Supplementary Fig. 6

Repression of a miR-133 sensor by miR-133 in C2C12 cells. (PDF 552 kb)

Supplementary Fig. 7

Sequences of the miR-1 and miR-133 target sites in the 3′ UTR of HDAC4 and SRF genes. (PDF 124 kb)

Supplementary Table 1

Sequences of oligonucleotides used in this study. (PDF 91 kb)

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Chen, JF., Mandel, E., Thomson, J. et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38, 228–233 (2006). https://doi.org/10.1038/ng1725

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  • DOI: https://doi.org/10.1038/ng1725

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