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.

The perfect storm of tiny RNAs

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Sulston, J.E., Schierenberg, E., White, J.G. & Thomson, J.N. The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev. Biol. 100, 64–119 (1983).

    PubMed  Article  CAS  Google Scholar 

  2. Sulston, J.E. & Horvitz, H.R. Abnormal cell lineages in mutants of the nematode Caenorhabditis elegans. Dev. Biol. 82, 41–55 (1981).

    PubMed  Article  CAS  Google Scholar 

  3. Chalfie, M., Horvitz, H.R. & Sulston, J.E. Mutations that lead to reiterations in the cell lineages of C. elegans. Cell 24, 59–69 (1981).

    PubMed  Article  CAS  Google Scholar 

  4. Ambros, V. & Horvitz, H.R. Heterochronic mutants of the nematode Caenorhabditis elegans. Science 226, 409–416 (1984).

    PubMed  Article  CAS  Google Scholar 

  5. Ambros, V. & Horvitz, H.R. The lin-14 locus of Caenorhabditis elegans controls the time of expression of specific postembryonic developmental events. Genes Dev. 1, 398–414 (1987).

    PubMed  Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Ruvkun, G. et al. Molecular genetics of the Caenorhabditis elegans heterochronic gene lin-14. Genetics 121, 501–516 (1989).

    PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. 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 C. elegans development. Genes Dev. 5, 1813–1824 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Arasu, P., Wightman, B. & Ruvkun, G. Temporal regulation of lin-14 by the antagonistic action of two other heterochronic genes, lin-4 and lin-28. Genes Dev. 5, 1825–1833 (1991).

    PubMed  Article  CAS  Google Scholar 

  11. 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Ha, I., Wightman, B. & Ruvkun, G. A bulged lin-4/lin-14 RNA duplex is sufficient for Caenorhabditis elegans lin-14 temporal gradient formation. Genes Dev. 10, 3041–3050 (1996).

    PubMed  Article  CAS  Google Scholar 

  14. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Lee, R.C. & Ambros, V. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862–864 (2001).

    PubMed  Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. 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  CAS  PubMed  Google Scholar 

  21. Grad, Y. et al. Computational and experimental identification of C. elegans microRNAs. Mol. Cell 11, 1253–1263 (2003).

    PubMed  Article  CAS  Google Scholar 

  22. Klattenhoff, C. & Theurkauf, W. Biogenesis and germline functions of piRNAs. Development 135, 3–9 (2008).

    PubMed  Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 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  CAS  PubMed  Google Scholar 

  26. Hutvágner, G. et al. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834–838 (2001).

    PubMed  Article  Google Scholar 

  27. Brodersen, P. et al. Widespread translational inhibition by plant miRNAs and siRNAs. Science 320, 1185–1190 (2008).

    PubMed  Article  CAS  Google Scholar 

  28. Chen, X. A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development. Science 303, 2022–2025 (2004).

    PubMed  Article  CAS  Google Scholar 

  29. Carrington, J.C. & Ambros, V. Role of microRNAs in plant and animal development. Science 301, 336–338 (2003).

    PubMed  Article  CAS  Google Scholar 

  30. Parry, D.H., Xu, J. & Ruvkun, G. A whole-genome RNAi screen for C. elegans miRNA pathway genes. Curr. Biol. 17, 2013–2022 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Kim, J.K. et al. Functional genomic analysis of RNA interference in C. elegans. Science 308, 1164–1167 (2005).

    PubMed  Article  CAS  Google Scholar 

  32. Kennedy, S., Wang, D. & Ruvkun, G. A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 427, 645–649 (2004).

    PubMed  Article  CAS  Google Scholar 

  33. Wang, D. et al. Somatic misexpression of germline P granules and enhanced RNA interference in C. elegans retinoblastoma pathway mutants. Nature 436, 593–597 (2005).

    PubMed  Article  CAS  Google Scholar 

  34. Fischer, S.E.J., Butler, M.D., Pan, Q. & Ruvkun, G. RNA duplex–mediated trans-splicing between independent mRNAs generates C. elegans ERI-6/7, a helicase that regulates RNAi. Nature (in the press).

  35. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Blower, M.D., Feric, E., Weis, K. & Heald, R. Genome-wide analysis demonstrates conserved localization of messenger RNAs to mitotic microtubules. J. Cell Biol. 179, 1365–1373 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. Buhtz, A., Springer, F., Chappell, L., Baulcombe, D.C. & Kehr, J. Identification and characterization of small RNAs from the phloem of Brassica napus. Plant J. 53, 739–749 (2008).

    PubMed  Article  CAS  Google Scholar 

  38. Jacobsen, S.E., Running, M.P. & Meyerowitz, E.M. Disruption of an RNA helicase/RNAse III gene in Arabidopsis causes unregulated cell division in floral meristems. Development 126, 5231–5243 (1999).

    PubMed  CAS  Google Scholar 

  39. 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  CAS  PubMed  Google Scholar 

  40. Viswanathan, S.R., Daley, G.Q. & Gregory, R.I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Newman, M.A., Thomson, J.M. & Hammond, S.M. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14, 1539–1549 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Richards, M., Tan, S.P., Tan, J.H., Chan, W.K. & Bongso, A. The transcriptome profile of human embryonic stem cells as defined by SAGE. Stem Cells 22, 51–64 (2004).

    PubMed  Article  CAS  Google Scholar 

  43. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Motamedi, M.R. et al. Two RNAi complexes, RITS and RDRC, physically interact and localize to noncoding centromeric RNAs. Cell 119, 789–802 (2004).

    PubMed  Article  CAS  Google Scholar 

  45. Cogoni, C. & Macino, G. Gene silencing in Neurospora crassa requires a protein homologous to RNA-dependent RNA polymerase. Nature 399, 166–169 (1999).

    PubMed  Article  CAS  Google Scholar 

  46. Mochizuki, K., Fine, N.A., Fujisawa, T. & Gorovsky, M.A. Analysis of a piwi-related gene implicates small RNAs in genome rearrangement in Tetrahymena. Cell 110, 689–699 (2002).

    PubMed  Article  CAS  Google Scholar 

  47. Ngo, H., Tschudi, C., Gull, K. & Ullu, E. Double-stranded RNA induces mRNA degradation in Trypanosoma brucei. Proc. Natl. Acad. Sci. USA 95, 14687–14692 (1998).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

Most important to the discoveries described here were the fantastic students, postdocs, technical, and administrative staff who created the lab. I would like to express my deepest gratitude to B. Wightman, I. Ha, P. Arasu, J. Giusto, J. Gatto, T. Burglin, B. Reinhart, A. Pasquinelli, F. Slack, S. Kennedy, D. Wang, J. Kim, H. Gabel, R. Kamath, S. Fischer, M. Butler, D. Parry, G. Hayes, X. Wu, C. Zhang, S. Garcia, C. Phillips and S. Curran on the tiny RNA team. An equal number of people on the aging, metabolism and Mars projects also contributed deeply to the intellectual and technical growth of the lab. I launched my lab in the Department of Molecular Biology at Massachusetts General Hospital under very special circumstances: we were completely funded by Hoechst from 1985 to 1992 and almost half funded by them for another decade. This level of patronage allowed us to embark on the study of an array of experimental problems that would have been much more difficult to tackle in a traditional grant-funded environment. H. Goodman deserves very special thanks for his decision to broaden this Hoechst-funded research beyond the endocrinology that was probably their original intent, and for his shrewd recruiting in so many fields. And I thank P. Leder for founding and settling the Department of Genetics at Harvard, my academic home, and my colleagues in the Department of Molecular Biology at Massachusetts General Hospital and the Department of Genetics at Harvard who taught me how to run a lab by their many examples of discovery and training of great scientists. I arrived at graduate school greener than green in 1976, and it was a combination of my fellow students, D. Hanahan, V. Sundaresan, W. Herr, G. Church and T. Wu, and my teachers, F. Ausubel, W. Gilbert, and R. Horvitz, who showed me how to become a scientist. During my postdoc, V. Ambros was my developmental genetics teacher and collaborator extraordinaire, our collaboration now extending over a career, and M. Finney was also a close collaborator, which extended to his postdoctoral work in my lab and current co-direction of our search for extraterrestrial genomes (SETG). So the tribes of my education, my lab and my academic environment were uniquely inspiring, supportive, and loads of fun. But my home tribe has been the wellspring of strength and joy: Natasha Staller is presumably the most sophisticated molecular geneticist among the world's art historians. As a historian of Cubism, she can see cultural inflection points that most do not, and after years of asking me about many details of our work, and reading most of our papers, she is also a very sophisticated biologist. From this vantage point, Natasha nudged me towards ambitious, high-risk projects, and her confidence in my abilities, and in the talents of my students and postdocs, incited a certain boldness. And I am truly grateful to Natasha and to our daughter Victoria for the joyous home life of our little tribe.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ruvkun, G. The perfect storm of tiny RNAs. Nat Med 14, 1041–1045 (2008). https://doi.org/10.1038/nm1008-1041

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1008-1041

This article is cited by

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