Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Commentary
  • Published:

The evolution of our thinking about microRNAs

Nature Medicine volume 14, pages 1036–1040 (2008)Cite this article

Should one example make the general case?

While these findings, in retrospect, were sufficient to define the essential characteristics of microRNA regulation of gene expression, there did not seem to be good reasons to think that there should necessarily be other small antisense RNAs like lin-4. Although it would have been great if lin-4 were an 'emissary' of other similar small noncoding regulatory RNAs yet to be discovered, as suggested by Takayama and Wickens7, as time went on I did not believe it would be so. We had no evidence for lin-4 sequences in organisms other than closely related nematodes6, and as lin-14, the target of lin-4, encoded a novel protein that was not particularly conserved outside of nematodes2, it seemed likely that the lin-4–lin-14 partnership could be just a nematode-specific curiosity.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phenotypes of lin-4 and lin-14 mutants.
Figure 2: C. elegans lin-4 and let-7 microRNAs and their predicted base-pairing with sites in the 3′ UTRs of lin-14 and lin-41 mRNAs, respectively.
Figure 3: Phylogenetic conservation of let-7 and lin-4 (miR-125), in sequence and genomic organization16,28,29,31.

References

  1. Ambros, V. A hierarchy of regulatory genes controls a larva-to-adult developmental switch in C. elegans. Cell 57, 49–57 (1989).

    Article  PubMed  Google Scholar 

  2. Ruvkun, G. & Giusto, J. The Caenorhabditis elegans heterochronic gene lin-14 encodes a nuclear protein that forms a temporal developmental switch. Nature 338, 313–319 (1989).

    Article  PubMed  Google Scholar 

  3. Lee, R.C., Feinbaum, R.L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    Article  PubMed  Google Scholar 

  4. Wightman, B., Bürglin, T.R., Gatto, J., Arasu, P. & Ruvkun, G. Negative regulatory sequences in the lin-14 3′-untranslated region are necessary to generate a temporal switch during Caenorhabditis elegans development. Genes Dev. 5, 1813–1824 (1991).

    Article  PubMed  Google Scholar 

  5. Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993).

    Article  PubMed  Google Scholar 

  6. Lee, R., Feinbaum, R. & Ambros, V. A short history of a short RNA. Cell 116, S89–S92 (2004).

    Article  PubMed  Google Scholar 

  7. Wickens, M. & Takayama, K. RNA. Deviants — or emissaries. Nature 367, 17–18 (1994).

    Article  PubMed  Google Scholar 

  8. Moss, E.G., Lee, R.C. & Ambros, V. The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA. Cell 88, 637–646 (1997).

    Article  PubMed  Google Scholar 

  9. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    Article  PubMed  Google Scholar 

  10. Hamilton, A.J. & Baulcombe, D.C. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286, 950–952 (1999).

    Article  PubMed  Google Scholar 

  11. Grishok, A. et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106, 23–34 (2001).

    Article  PubMed  Google Scholar 

  12. Reinhart, B.J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).

    Article  PubMed  Google Scholar 

  13. Slack, F.J. et al. The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Mol. Cell 5, 659–669 (2000).

    Article  PubMed  Google Scholar 

  14. Ambros, V., Lee, R.C., Lavanway, A., Williams, P.T. & Jewell, D. MicroRNAs and other tiny endogenous RNAs in C. elegans. Curr. Biol. 13, 807–818 (2003).

    Article  PubMed  Google Scholar 

  15. 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  PubMed  Google Scholar 

  16. Pasquinelli, A.E. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000).

    Article  PubMed  Google Scholar 

  17. Elbashir, S.M., Lendeckel, W. & Tuschl, T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev. 15, 188–200 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).

    Article  PubMed  Google Scholar 

  19. Lau, N.C., Lim, L.P., Weinstein, E.G. & Bartel, D.P. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858–862 (2001).

    Article  PubMed  Google Scholar 

  20. Lewis, B.P., Burge, C.B. & Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  PubMed  Google Scholar 

  21. Grosshans, H., Johnson, T., Reinert, K.L., Gerstein, M. & Slack, F.J. The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans. Dev. Cell 8, 321–330 (2005).

    Article  PubMed  Google Scholar 

  22. Lall, S. et al. A genome-wide map of conserved microRNA targets in C. elegans. Curr. Biol. 16, 460–471 (2006).

    Article  PubMed  Google Scholar 

  23. Lewis, B.P., Shih, I.H., Jones-Rhoades, M.W., Bartel, D.P. & Burge, C.B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).

    Article  PubMed  Google Scholar 

  24. Heimberg, A.M., Sempere, L.F., Moy, V.N., Donoghue, P.C. & Peterson, K.J. MicroRNAs and the advent of vertebrate morphological complexity. Proc. Natl. Acad. Sci. USA 105, 2946–2950 (2008).

    Article  PubMed  Google Scholar 

  25. Brennecke, J., Stark, A., Russell, R.B. & Cohen, S.M. Principles of microRNA–target recognition. PLoS Biol. 3, e85 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Doench, J.G. & Sharp, P.A. Specificity of microRNA target selection in translational repression. Genes Dev. 18, 504–511 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bashirullah, A. et al. Coordinate regulation of small temporal RNAs at the onset of Drosophila metamorphosis. Dev. Biol. 259, 1–8 (2003).

    Article  PubMed  Google Scholar 

  28. Sempere, L.F., Sokol, N.S., Dubrovsky, E.B., Berger, E.M. & Ambros, V. Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and Broad-Complex gene activity. Dev. Biol. 259, 9–18 (2003).

    Article  PubMed  Google Scholar 

  29. Sokol, N.S., Xu, P., Jan, Y.N. & Ambros, V. Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis. Genes Dev. 22, 1591–1596 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chen, K. & Rajewsky, N. Deep conservation of microRNA-target relationships and 3′UTR motifs in vertebrates, flies, and nematodes. Cold Spring Harb. Symp. Quant. Biol. 71, 149–156 (2006).

    Article  PubMed  Google Scholar 

  31. Prochnik, S.E., Rokhsar, D.S. & Aboobaker, A.A. Evidence for a microRNA expansion in the bilaterian ancestor. Dev. Genes Evol. 217, 73–77 (2007).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The research in my laboratory has been supported by US National Institutes of Health grants RO1 GM34028 and GM066826. I am deeply grateful to many colleagues, collaborators, students, postdocs, family and friends whose ideas and efforts brought about the science reviewed here and who have, thereby and otherwise, so vitally supported me. I am enormously fortunate to have had extraordinary mentors at every stage in my career. Finally, I want to particularly thank Rosalind Lee for our enduring personal and scientific partnership. Without you, nothing—with you, everything.

Author information

Authors and Affiliations

  1. Victor Ambros is at the University of Massachusetts Medical School Department of Molecular Medicine, 373 Plantation Street, B2-306, Worcester, Massachusetts 01605, USA. victor.ambros@umassmed.edu,

    Victor Ambros

Authors
  1. Victor Ambros
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ambros, V. The evolution of our thinking about microRNAs. Nat Med 14, 1036–1040 (2008). https://doi.org/10.1038/nm1008-1036

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1008-1036

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing