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 functions of animal microRNAs

Abstract

MicroRNAs (miRNAs) are small RNAs that regulate the expression of complementary messenger RNAs. Hundreds of miRNA genes have been found in diverse animals, and many of these are phylogenetically conserved. With miRNA roles identified in developmental timing, cell death, cell proliferation, haematopoiesis and patterning of the nervous system, evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Examples of the imprecise base pairing of animal miRNAs with their targets.
Figure 2: Approaches to miRNA gene discovery and the functional characterization of miRNA genes.
Figure 3: The roles of miRNAs lsy-6 and mir-273 in the pathway specifying the sensory neuron cell fates ASEL and ASER28,29,30.

References

  1. 1

    Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Hutvágner, G. & Zamore, P. D. A microRNA in a multiple-turnover RNAi enzyme complex. Science 297, 2056–2060 (2002).

    ADS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Zeng, Y., Wagner, E. J. & Cullen, B. R. Both natural and designed microRNAs can inhibit the expression of cognate mRNAs when expressed in human cells. Mol. Cell 9, 1327–1333 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Zeng, Y., Yi, R. & Cullen, B. R. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc. Natl Acad. Sci. USA 100, 9779–9784 (2003).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Rhoades, M. W. et al. Prediction of plant microRNA targets. Cell 110, 513–520 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Tang, G., Reinhart, B. J., Bartel, D. P. & Zamore, P. D. A biochemical framework for RNA silencing in plants. Genes Dev. 17, 49–63 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    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).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Seggerson, K., Tang, L. & Moss, E. G. Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation. Dev. Biol. 243, 215–225 (2002).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    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).

    ADS  CAS  Article  Google Scholar 

  11. 11

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

    ADS  CAS  Article  Google Scholar 

  12. 12

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

    ADS  CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Lai, E. C., Tomancak, P., Williams, R. W. & Rubin, G. M. Computational identification of Drosophila microRNA genes. Genome Biol. 4(R42), 1–20 (2003).

    Google Scholar 

  15. 15

    Lim, L. P. et al. The microRNAs of Caenorhabditis elegans. Genes Dev. 17, 991–1008 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W. & Tuschl, T. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Lagos-Quintana, M., Rauhut, R., Meyer, J., Borkhardt, A. & Tuschl, T. New microRNAs from mouse and human. RNA 9, 175–179 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Lim, L. P., Glasner, M. E., Yekta, S., Burge, C. B. & Bartel, D. P. Vertebrate microRNA genes. Science 299, 1540 (2003).

    CAS  Article  Google Scholar 

  19. 19

    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).

    CAS  Article  PubMed  Google Scholar 

  20. 20

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

    ADS  CAS  Article  Google Scholar 

  21. 21

    Ambros, V. et al. A uniform system for microRNA annotation. RNA 9, 277–279 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    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).

    CAS  Article  Google Scholar 

  25. 25

    Hipfner, D. R., Weigmann, K. & Cohen, S. M. The bantam gene regulates Drosophila growth. Genetics 161, 1527–1537 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B. & Cohen, S. M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Xu, P., Vernooy, S. Y., Guo, M. & Hay, B. A. The Drosophila microRNA mir-14 suppresses cell death and is required for normal fat metabolism. Curr. Biol. 13, 790–795 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Chang, S., Johnston, R. J. Jr & Hobert, O. A transcriptional regulatory cascade that controls left/right asymmetry in chemosensory neurons of C. elegans. Genes Dev. 17, 2123–2137 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Johnston, R. J. & Hobert, O. A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426, 845–849 (2003).

    ADS  CAS  Article  Google Scholar 

  30. 30

    Chang, S., Johnston, R. J. Jr, Frøkjær-Jensen, C., Lockery, S. & Hobert, O. MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode. Nature 430, 785–798 (2004).

    ADS  CAS  Article  Google Scholar 

  31. 31

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

    CAS  Article  PubMed  Google Scholar 

  32. 32

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

    CAS  Article  PubMed  Google Scholar 

  33. 33

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

    ADS  CAS  Article  PubMed  Google Scholar 

  34. 34

    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).

    CAS  Article  PubMed  Google Scholar 

  35. 35

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

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Feinbaum, R. & Ambros, V. The timing of lin-4 RNA accumulation controls the timing of postembryonic developmental events in Caenorhabditis elegans. Dev. Biol. 210, 87–95 (1999).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Seitz, H. et al. Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nature Genet. 34, 261–262 (2003).

    ADS  CAS  Article  Google Scholar 

  38. 38

    Bartel, D. P. & Chen, C. -Z. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nature Rev. Genet. 5, 396–401 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Stark, A., Brennecke, J., Russell, R. B. & Cohen, S. M. Identification of Drosophila microRNA targets. PLoS Biol. 1, E60 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Enright, A. J. et al. MicroRNA targets in Drosophila. Genome Biol. 5, R1 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Rajewskya, N. & Socci, N. D. Computational identification of microRNA targets. Dev. Biol. 267, 529–535 (2004).

    Article  Google Scholar 

  42. 42

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Kiriakidou, M. et al. A combined computational-experimental approach predicts human microRNA targets. Genes Dev. 18, 1165–1178 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Vella, M. C., Choi, E. Y., Lin, S. Y., Reinert, K. & Slack, F. J. The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3′ UTR. Genes Dev. 18, 32–37 (2004).

    Article  Google Scholar 

  45. 45

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Moss, E. G. & Tang, L. Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites. Dev. Biol. 258, 432–442 (2003).

    CAS  Article  PubMed  Google Scholar 

  47. 47

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

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Abrahante, J. E. et al. The Caenorhabditis elegans hunchback-like gene lin-57/hbl-1 controls developmental time and is regulated by microRNAs. Dev. Cell 4, 625–637 (2003).

    CAS  Article  Google Scholar 

  49. 49

    Lin, S. Y. et al. The C. elegans hunchback homolog, hbl-1, controls temporal patterning and is a probable microRNA target. Dev. Cell 4, 639–650 (2003).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Hutvágner, G., Simard, M. J., Mello, C. C. & Zamore, P. D. Sequence-specific inhibition of small RNA function. PLoS Biol. 2, E98 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank members of the Ambros laboratory and numerous other colleagues for stimulating discussions. V.A. is supported by NIH grants.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004). https://doi.org/10.1038/nature02871

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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