Abstract
Deciphering the mechanisms underlying skeletal muscle-cell differentiation in mammals is an important challenge. Cell differentiation involves complex pathways regulated at both transcriptional and post-transcriptional levels. Recent observations have revealed the importance of small (20–25 base pair) non-coding RNAs (microRNAs or miRNAs) that are expressed in both lower organisms1 and in mammals2,3. miRNAs modulate gene expression by affecting mRNA translation4 or stability5. In lower organisms, miRNAs are essential for cell differentiation during development6,7,8,9; some miRNAs are involved in maintenance of the differentiated state. Here, we show that miR-181, a microRNA that is strongly upregulated during differentiation, participates in establishing the muscle phenotype. Moreover, our results suggest that miR-181 downregulates the homeobox protein Hox-A11 (a repressor of the differentiation process), thus establishing a functional link between miR-181 and the complex process of mammalian skeletal-muscle differentiation. Therefore, miRNAs can be involved in the establishment of a differentiated phenotype — even when they are not expressed in the corresponding fully differentiated tissue.
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References
Ambros, V. microRNAs: tiny regulators with great potential. Cell 107, 823–826 (2001).
Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).
Lagos-Quintana, M. et al. New microRNAs from mouse and human. RNA 9, 175–179 (2003).
Olsen, P. H. & Ambros, V. The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev. Biol. 216, 671–680 (1999).
Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).
Krichevsky, A. M. et al. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9, 1274–1281 (2003).
Houbaviy, H. B., Murray, M. F. & Sharp, P. A. Embryonic stem cell-specific microRNAs. Dev. Cell 5, 351–358 (2003).
Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).
Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004).
Dinsmore, J. et al. Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell Transplant. 5, 131–143 (1996).
Koshkin, A. A. et al. LNA (Locked Nucleic Acid): An RNA mimic forming exceedingly stable LNA:LNA duplexes. J. Am. Chem. Soc. 120, 13252–13260 (1998).
Sempere, L. F. et al. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. 5, R13 (2004).
Hutvagner, G., Simard, M. J., Mello, C. & Zamore, P. Sequence-specific inhibition of small RNA function. PLOS Biology 2, 1–11 (2004).
Meister, G., Landthaler, M., Dorsett, Y. & Tuschl, T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544–550 (2004).
Wahlestedt, C. et al. Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proc. Natl Acad. Sci. USA 97, 5633–5638 (2000).
Fuchtbauer, E. M. & Westphal, H. MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse. Dev. Dyn. 193, 34–39 (1992).
Lewis, B. P. et al. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).
Rehmsmeier, M., Steffen, P., Hochsmann, M. & Giegerich, R. Fast and effective prediction of microRNA–target duplexes. RNA 10, 1507–1517 (2004).
Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005).
Patterson, L. T., Pembaur, M. & Potter, S. S. Hoxa11 and Hoxd11 regulate branching morphogenesis of the ureteric bud in the developing kidney. Development 128, 2153–2161 (2001).
Small, K. M. & Potter, S. S. Homeotic transformations and limb defects in Hox A11 mutant mice. Genes Dev. 7, 2318–2328 (1993).
Yamamoto, M. et al. Coordinated expression of Hoxa-11 and Hoxa-13 during limb muscle patterning. Development 125, 1325–1335 (1998).
Yamamoto, M. & Kuroiwa, A. Hoxa-11 and Hoxa-13 are involved in repression of MyoD during limb muscle development. Dev. Growth Differ. 45, 485–498 (2003).
Takahashi, Y. et al. Expression profiles of 39 HOX genes in normal human adult organs and anaplastic thyroid cancer cell lines by quantitative real-time RT–PCR system. Exp. Cell Res. 293, 144–153 (2004).
Poy, M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).
Doench, J. G., Petersen, C. P. & Sharp, P. A. siRNAs can function as miRNAs. Genes Dev. 17, 438–442 (2003).
Pillai, R. S. et al. Inhibition of translational initiation by Let-7 microRNA in human cells. Science 309, 1573–1576 (2005).
Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005).
Polesskaya, A., Seale, P. & Rudnicki, M. A. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell 113, 841–852 (2003).
DeNardi, C. et al. Type 2X-myosin heavy chain is coded by a muscle fibre type-specific and developmentally regulated gene. J. Cell Biol. 123, 823–835 (1993).
Acknowledgements
We are grateful to S. Shiaffino and to Ambion for useful technical advices; to S. Kaupinen (Exiqon), K. Arar, A. Chauchereau and M. Gerard for the kind gift of reagents, and to L. L. Pritchard, A. Hamiche and J. B. Weitzman for critical reading of the manuscript. This work was supported by the Ligue contre le Cancer and the European Union's 6th Framework Program (grant number LSHB-CT-2004-005276).
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Naguibneva, I., Ameyar-Zazoua, M., Polesskaya, A. et al. The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation. Nat Cell Biol 8, 278–284 (2006). https://doi.org/10.1038/ncb1373
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DOI: https://doi.org/10.1038/ncb1373
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