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The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation

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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Figure 1: miR-181 is expressed in muscle.
Figure 2: Inhibition of miR-181 affects myoblast differentiation.
Figure 3: Hox-A11 expression pattern in muscle.
Figure 4: Hox-A11 is a target for miR-181.
Figure 5: miR-181 pathway in terminally differentiating myoblasts.

References

  1. Ambros, V. microRNAs: tiny regulators with great potential. Cell 107, 823–826 (2001).

    Article  CAS  Google Scholar 

  2. Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).

    Article  CAS  Google Scholar 

  3. Lagos-Quintana, M. et al. New microRNAs from mouse and human. RNA 9, 175–179 (2003).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).

    Article  CAS  Google Scholar 

  6. Krichevsky, A. M. et al. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9, 1274–1281 (2003).

    Article  CAS  Google Scholar 

  7. Houbaviy, H. B., Murray, M. F. & Sharp, P. A. Embryonic stem cell-specific microRNAs. Dev. Cell 5, 351–358 (2003).

    Article  CAS  Google Scholar 

  8. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    Article  CAS  Google Scholar 

  9. Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004).

    Article  CAS  Google Scholar 

  10. Dinsmore, J. et al. Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell Transplant. 5, 131–143 (1996).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    Article  Google Scholar 

  13. Hutvagner, G., Simard, M. J., Mello, C. & Zamore, P. Sequence-specific inhibition of small RNA function. PLOS Biology 2, 1–11 (2004).

    Article  Google Scholar 

  14. Meister, G., Landthaler, M., Dorsett, Y. & Tuschl, T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544–550 (2004).

    Article  CAS  Google Scholar 

  15. Wahlestedt, C. et al. Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proc. Natl Acad. Sci. USA 97, 5633–5638 (2000).

    Article  CAS  Google Scholar 

  16. Fuchtbauer, E. M. & Westphal, H. MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse. Dev. Dyn. 193, 34–39 (1992).

    Article  CAS  Google Scholar 

  17. Lewis, B. P. et al. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).

    Article  CAS  Google Scholar 

  18. Rehmsmeier, M., Steffen, P., Hochsmann, M. & Giegerich, R. Fast and effective prediction of microRNA–target duplexes. RNA 10, 1507–1517 (2004).

    Article  CAS  Google Scholar 

  19. Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005).

    Article  CAS  Google Scholar 

  20. 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).

    CAS  PubMed  Google Scholar 

  21. Small, K. M. & Potter, S. S. Homeotic transformations and limb defects in Hox A11 mutant mice. Genes Dev. 7, 2318–2328 (1993).

    Article  CAS  Google Scholar 

  22. Yamamoto, M. et al. Coordinated expression of Hoxa-11 and Hoxa-13 during limb muscle patterning. Development 125, 1325–1335 (1998).

    CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Poy, M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).

    Article  CAS  Google Scholar 

  26. Doench, J. G., Petersen, C. P. & Sharp, P. A. siRNAs can function as miRNAs. Genes Dev. 17, 438–442 (2003).

    Article  CAS  Google Scholar 

  27. Pillai, R. S. et al. Inhibition of translational initiation by Let-7 microRNA in human cells. Science 309, 1573–1576 (2005).

    Article  CAS  Google Scholar 

  28. Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

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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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Correspondence to Annick Harel-Bellan.

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Supplementary figures S1, S2a to S2c and S3a to S3d (PDF 105 kb)

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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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