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.

  • Progress
  • Published:

Endogenous small interfering RNAs in animals

Nature Reviews Molecular Cell Biology volume 9, pages 673–678 (2008)Cite this article

Abstract

Until recently, only nematodes among animals had a well-defined endogenous small interfering RNA (endo-siRNA) pathway. This has changed dramatically with the recent discovery of diverse intramolecular and intermolecular substrates that generate endo-siRNAs in Drosophila melanogaster and mice. These findings suggest broad and possibly conserved roles for endogenous RNA interference in regulating host-gene expression and transposable element transcripts. They also raise many questions regarding the biogenesis and function of small regulatory RNAs in animals.

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

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: Small RNA pathways in Drosophila melanogaster.
Figure 2: Specialized small-RNA regulatory pathways in the animal germ line.
Figure 3: Nematode small interfering RNA pathways.
Figure 4: Substrates for endo-siRNA production in flies and mouse.

Similar content being viewed by others

References

  1. Lee, Y. S. et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117, 69–81 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Okamura, K., Ishizuka, A., Siomi, H. & Siomi, M. C. Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes Dev. 18, 1655–1666 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Tabara, H. et al. The rde-1 gene, RNA interference, and transposon silencing in C. elegans. Cell 99, 123–132 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Tabara, H., Yigit, E., Siomi, H. & Mello, C. C. The dsRNA binding protein RDE-4 interacts with RDE-1, DCR-1, and a DExH-box helicase to direct RNAi in C. elegans. Cell 109, 861–871 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Ding, S. W. & Voinnet, O. Antiviral immunity directed by small RNAs. Cell 130, 413–426 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Tam, O. H. et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534–538 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Watanabe, T. et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453, 539–543 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Ghildiyal, M. et al. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells. Science 320, 1077–1081 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Okamura, K., Balla, S., Martin, R., Liu, N. & Lai, E. C. Two distinct mechanisms generate endogenous siRNAs from bidirectional transcription in Drosophila. Nature Struct. Mol. Biol. 15, 581–590 (2008).

    Article  CAS  Google Scholar 

  10. Okamura, K. et al. The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs. Nature 453, 803–806 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Kawamura, Y. et al. Drosophila endogenous small RNAs bind to Argonaute2 in somatic cells. Nature 453, 793–797 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Czech, B. et al. An endogenous siRNA pathway in Drosophila. Nature 453, 798–802 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Chung, W. J., Okamura, K., Martin, R. & Lai, E. C. Endogenous RNA interference provides a somatic defense against Drosophila transposons. Current Biology 18, 795–802 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Farazi, T. A., Juranek, S. A. & Tuschl, T. The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members. Development 135, 1201–1214 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Mourelatos, Z. et al. miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 16, 720–728 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Meister, G. et al. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15, 185–197 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Saito, K. et al. Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes Dev. 20, 2214–2222 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Gunawardane, L. S. et al. A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science 315, 1587–1590 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Lau, N. C. et al. Characterization of the piRNA complex from rat testes. Science 313, 363–367 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Ruby, J. G. et al. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 127, 1193–207 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Pak, J. & Fire, A. Distinct populations of primary and secondary effectors during RNAi in C. elegans. Science 315, 241–244 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Sijen, T., Steiner, F. A., Thijssen, K. L. & Plasterk, R. H. Secondary siRNAs result from unprimed RNA synthesis and form a distinct class. Science 315, 244–247 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Yigit, E. et al. Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi. Cell 127, 747–757 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Wang, G. & Reinke, V. A C. elegans Piwi, PRG-1, regulates 21U-RNAs during spermatogenesis. Curr. Biol. 18, 861–867 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Batista, P. J. et al. PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans. Mol. Cell 31, 67–78 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Das, P. P. et al. Piwi and piRNAs act upstream of an endogenous siRNA pathway to suppress Tc3 transposon mobility in the Caenorhabditis elegans germline. Mol. Cell 31, 79–90 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Aravin, A. A., Hannon, G. J. & Brennecke, J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318, 761–764 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Ketting, R. F., Haverkamp, T. H., van Luenen, H. G. & Plasterk, R. H. Mut-7 of C. elegans, required for transposon silencing and RNA interference, is a homolog of Werner syndrome helicase and RNaseD. Cell 99, 133–141 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Sijen, T. & Plasterk, R. H. Transposon silencing in the Caenorhabditis elegans germ line by natural RNAi. Nature 426, 310–314 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Kuramochi-Miyagawa, S. et al. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131, 839–849 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Carmell, M. A. et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev. Cell 12, 503–514 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Deng, W. & Lin, H. miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev. Cell 2, 819–830 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Murchison, E. P. et al. Critical roles for Dicer in the female germline. Genes Dev. 21, 682–693 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Svoboda, P. et al. RNAi and expression of retrotransposons MuERV-L and IAP in preimplantation mouse embryos. Dev. Biol. 269, 276–285 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Watanabe, T. et al. Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. Genes Dev. 20, 1732–1743 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Yang, N. & Kazazian, H. H. Jr. L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nature Struct. Mol. Biol. 13, 763–771 (2006).

    Article  CAS  Google Scholar 

  39. Svoboda, P., Stein, P., Hayashi, H. & Schultz, R. M. Selective reduction of dormant maternal mRNAs in mouse oocytes by RNA interference. Development 127, 4147–4156 (2000).

    CAS  PubMed  Google Scholar 

  40. Stein, P., Zeng, F., Pan, H. & Schultz, R. M. Absence of non-specific effects of RNA interference triggered by long double-stranded RNA in mouse oocytes. Dev. Biol. 286, 464–471 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Reinhart, B. J., Weinstein, E. G., Rhoades, M. W., Bartel, B. & Bartel, D. P. MicroRNAs in plants. Genes Dev. 16, 1616–1626 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Ruby, J. G. et al. Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs. Genome Res. 17, 1850–1864 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Liu, Q. et al. R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway. Science 301, 1921–5 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Tomari, Y., Matranga, C., Haley, B., Martinez, N. & Zamore, P. D. A protein sensor for siRNA asymmetry. Science 306, 1377–1380 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Jiang, F. et al. Dicer-1 and R3D1-L catalyze microRNA maturation in Drosophila. Genes Dev. 19, 1674–1679 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Forstemann, K. et al. Normal microRNA maturation and germ-line stem cell maintenance requires Loquacious, a double-stranded RNA-binding domain protein. PLoS Biol. 3, e236 (2005).

    Article  PubMed Central  PubMed  Google Scholar 

  47. Saito, K., Ishizuka, A., Siomi, H. & Siomi, M. C. Processing of pre-microRNAs by the Dicer-1–Loquacious complex in Drosophila cells. PLoS Biol. 3, e235 (2005).

    Article  PubMed Central  PubMed  Google Scholar 

  48. Kalidas, S. et al. Drosophila R2D2 mediates follicle formation in somatic tissues through interactions with Dicer-1. Mech. Dev. 125, 475–85 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Meyer, W. J. et al. Overlapping functions of argonaute proteins in patterning and morphogenesis of Drosophila embryos. PLoS Genet. 2, e134 (2006).

    Article  PubMed Central  PubMed  Google Scholar 

  50. Seitz, H., Ghildiyal, M. & Zamore, P. D. Argonaute loading improves the 5′ precision of both microRNAs and their miRNA strands in flies. Curr. Biol. 18, 147–151 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Forstemann, K., Horwich, M. D., Wee, L., Tomari, Y. & Zamore, P. D. Drosophila microRNAs are sorted into functionally distinct argonaute complexes after production by dicer-1. Cell 130, 287–297 (2007).

    Article  PubMed Central  PubMed  Google Scholar 

  52. Horwich, M. D. et al. The Drosophila RNA methyltransferase, DmHen1, modifies germline piRNAs and single-stranded siRNAs in RISC. Curr. Biol. 17, 1265–1272 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Liu, X. et al. Dicer-1, but not Loquacious, is critical for assembly of miRNA-induced silencing complexes. RNA 13, 2324–2329 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Sunkar, R., Girke, T., Jain, P. K. & Zhu, J. K. Cloning and characterization of microRNAs from rice. Plant Cell 17, 1397–1411 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Paddison, P. J., Caudy, A. A. & Hannon, G. J. Stable suppression of gene expression by RNAi in mammalian cells. Proc. Natl Acad. Sci. USA 99, 1443–1448 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Yang, S., Tutton, S., Pierce, E. & Yoon, K. Specific double-stranded RNA interference in undifferentiated mouse embryonic stem cells. Mol. Cell. Biol. 21, 7807–7816 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Calabrese, J. M., Seila, A. C., Yeo, G. W. & Sharp, P. A. RNA sequence analysis defines Dicer's role in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 104, 18097–18102 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mi, S. et al. Sorting of small RNAs into Arabidopsis argonaute complexes is directed by the 5′ terminal nucleotide. Cell 133, 116–127 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Montgomery, T. A. et al. Specificity of ARGONAUTE7–miR390 interaction and dual functionality in TAS3 trans-acting siRNA formation. Cell 133, 128–141 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Jannot, G., Boisvert, M. E., Banville, I. H. & Simard, M. J. Two molecular features contribute to the Argonaute specificity for the microRNA and RNAi pathways in C. elegans. RNA 14, 829–835 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Steiner, F. A. et al. Structural features of small RNA precursors determine Argonaute loading in Caenorhabditis elegans. Nature Struct. Mol. Biol. 14, 927–933 (2007).

    Article  CAS  Google Scholar 

  62. Tomari, Y., Du, T. & Zamore, P. D. Sorting of Drosophila small silencing RNAs. Cell 130, 299–308 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Azuma-Mukai, A. et al. Characterization of endogenous human Argonautes and their miRNA partners in RNA silencing. Proc. Natl Acad. Sci. USA 105, 7964–7969 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. O'Carroll, D. et al. A slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev. 21, 1999–2004 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Diederichs, S. & Haber, D. A. Dual role for argonautes in microRNA processing and posttranscriptional regulation of microRNA expression. Cell 131, 1097–1108 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Spike, C. A., Bader, J., Reinke, V. & Strome, S. DEPS-1 promotes P-granule assembly and RNA interference in C. elegans germ cells. Development 135, 983–993 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Grishok, A. & Sharp, P. A. Negative regulation of nuclear divisions in Caenorhabditis elegans by retinoblastoma and RNA interference-related genes. Proc. Natl Acad. Sci. USA 102, 17360–17365 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Peng, J. C. & Karpen, G. H. H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nature Cell Biol. 9, 25–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Deshpande, G., Calhoun, G. & Schedl, P. Drosophila argonaute-2 is required early in embryogenesis for the assembly of centric/centromeric heterochromatin, nuclear division, nuclear migration, and germ-cell formation. Genes Dev. 19, 1680–1685 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Tang, F. et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev. 21, 644–648 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

K.O. was supported by the Charles Revson Foundation. E.C.L. was supported by the V Foundation for Cancer Research, the Sidney Kimmel Foundation for Cancer Research, the Alfred Bressler Scholars Fund and the National Institutes of Health (GM083300).

Author information

Authors and Affiliations

  1. Department of Developmental Biology, Katsutomo Okamura and Eric C. Lai are at the Sloan-Kettering Institute, 521 Rockefeller Research Laboratories, 1275 York Avenue, BOX 252, New York, New York 10065, USA.,

    Katsutomo Okamura & Eric C. Lai

Authors
  1. Katsutomo Okamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric C. Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric C. Lai.

Related links

Related links

FURTHER INFORMATION

Eric C. Lai's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okamura, K., Lai, E. Endogenous small interfering RNAs in animals. Nat Rev Mol Cell Biol 9, 673–678 (2008). https://doi.org/10.1038/nrm2479

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2479

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