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.

  • Review Article
  • Published:

MicroRNAs: small RNAs with a big role in gene regulation

A Correction to this article was published on 01 August 2004

Key Points

  • MicroRNAs (miRNAs) are a family of 21–25-nucleotide small RNAs that negatively regulate gene expression at the post-transcriptional level.

  • The founding members of the miRNA family, lin-4 and let-7, were identified through genetic screens for defects in the temporal regulation of Caenorhabditis elegans larval development.

  • Owing to genome-wide cloning efforts, hundreds of miRNAs have now been identified in almost all metazoans, including flies, plants and mammals.

  • MiRNAs exhibit temporally and spatially regulated expression patterns during diverse developmental and physiological processes.

  • Most of the miRNAs that have been characterized so far seem to regulate aspects of development, including larval developmental transitions and neuronal development in C. elegans, growth control and apoptosis in Drosophila melanogaster, haematopoietic differentiation in mammals, and leaf development, flower development and embryogenesis in Arabidopsis thaliana.

  • The majority of the animal miRNAs that have been characterized so far affect protein synthesis from their target mRNAs. On the other hand, most of the plant miRNAs studied so far direct the cleavage of their targets.

  • The degree of complementarity between a miRNA and its target, at least in part, determines the regulatory mechanism.

  • In animals, primary transcripts of miRNAs are processed sequentially by two RNase-III enzymes, Drosha and Dicer, into a small, imperfect dsRNA duplex (miRNA:miRNA*) that contains both the mature miRNA strand and its complementary strand (miRNA*). Relative instability at the 5′ end of the mature miRNA leads to the asymmetric assembly of the mature miRNA into the effector complex, the RNA-induced silencing complex (RISC).

  • Ago proteins are a key component of the RISC. Multiple Ago homologues in various metazoan genomes indicate the existence of multiple RISCs that carry out related but specific biological functions.

  • Bioinformatic prediction of miRNA targets has provided an important tool to explore the functions of miRNAs. However, the overall success rate of such predictions remains to be determined by experimental validation.

Abstract

MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Since then, hundreds of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. MicroRNAs have diverse expression patterns and might regulate various developmental and physiological processes. Their discovery adds a new dimension to our understanding of complex gene regulatory networks.

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

Access options

Buy this article

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

Figure 1: The molecular hallmarks of lin-4, the founding member of the microRNA family.
Figure 2: The current model for the biogenesis and post-transcriptional suppression of microRNAs and small interfering RNAs.
Figure 3: The structure and function of the Dicer family.

Similar content being viewed by others

References

  1. del Solar, G. & Espinosa, M. Plasmid copy number control: an ever-growing story. Mol. Microbiol. 37, 492–500 (2000).

    CAS  PubMed  Google Scholar 

  2. Mlynarczyk, S. K. & Panning, B. X inactivation: Tsix and Xist as yin and yang. Curr. Biol. 10, R899–R903 (2000).

    CAS  PubMed  Google Scholar 

  3. Ambros, V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 113, 673–676 (2003).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Lai, E. C. microRNAs: runts of the genome assert themselves. Curr. Biol. 13, R925–R936 (2003).

    CAS  PubMed  Google Scholar 

  6. Pasquinelli, A. E. & Ruvkun, G. Control of developmental timing by micrornas and their targets. Annu. Rev. Cell Dev. Biol. 18, 495–513 (2002).

    CAS  PubMed  Google Scholar 

  7. McManus, M. T. MicroRNAs and cancer. Semin. Cancer Biol. 13, 253–258 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. 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). Described the identification of the first microRNA, lin-4 , and reported the sequence complementarity between lin-4 and the 3′ UTR of the lin-14 mRNA.

    CAS  PubMed  Google Scholar 

  14. Wightman, B., Burglin, 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).

    CAS  PubMed  Google Scholar 

  15. 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).

    CAS  PubMed  Google Scholar 

  16. 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  PubMed  Google Scholar 

  17. 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).

    CAS  PubMed  Google Scholar 

  18. 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). Described the translational repression of LIN-14 by lin-4 during temporal regulation of larval development. This was the first functional characterization of a microRNA.

    CAS  PubMed  Google Scholar 

  19. 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  PubMed  Google Scholar 

  20. 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 

  21. 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  PubMed  Google Scholar 

  22. 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  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  24. 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, 132–137 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003). Described the identification of Drosha and characterizes its function in processing pri-miRNA into pre-miRNA.

    CAS  PubMed  Google Scholar 

  29. Lee, Y., Jeon, K., Lee, J. T., Kim, S. & Kim, V. N. MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 21, 4663–4670 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hannon, G. J. RNA interference. Nature 418, 244–251 (2002).

    CAS  PubMed  Google Scholar 

  31. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zamore, P. D., Tuschl, T., Sharp, P. A. & Bartel, D. P. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25–33 (2000).

    CAS  PubMed  Google Scholar 

  34. Baulcombe, D. Viruses and gene silencing in plants. Arch. Virol. 15 (Suppl.), 189–201 (1999).

    CAS  Google Scholar 

  35. Aufsatz, W., Mette, M. F., van der Winden, J., Matzke, A. J. & Matzke, M. RNA-directed DNA methylation in Arabidopsis. Proc. Natl Acad. Sci. USA 99 (Suppl 4), 16499–16506 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Mette, M. F., Aufsatz, W., van der Winden, J., Matzke, M. A. & Matzke, A. J. Transcriptional silencing and promoter methylation triggered by double-stranded RNA. EMBO J. 19, 5194–5201 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Grewal, S. I. & Moazed, D. Heterochromatin and epigenetic control of gene expression. Science 301, 798–802 (2003).

    CAS  PubMed  Google Scholar 

  38. Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002).

    CAS  PubMed  Google Scholar 

  39. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Llave, C., Xie, Z., Kasschau, K. D. & Carrington, J. C. Cleavage of Scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science 297, 2053–2056 (2002).

    CAS  PubMed  Google Scholar 

  43. Rhoades, M. W. et al. Prediction of plant microRNA targets. Cell 110, 513–520 (2002). The first bioinfomatic effort to predict microRNA targets on the basis of sequence complementarity between plant miRNAs and their putative targets. It has guided functional studies of several miRNAs.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 (2001). Described the identification of Dicer and characterized its function in processing long dsRNAs into small interfering RNAs.

    CAS  PubMed  Google Scholar 

  47. Hutvagner, 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).

    CAS  PubMed  Google Scholar 

  48. Hammond, S. M., Boettcher, S., Caudy, A. A., Kobayashi, R. & Hannon, G. J. Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293, 1146–1150 (2001). Described the purification of the RISC, and the identification of Argonaute 2 as a key component.

    CAS  PubMed  Google Scholar 

  49. Caudy, A. A., Myers, M., Hannon, G. J. & Hammond, S. M. Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev. 16, 2491–2496 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Dostie, J., Mourelatos, Z., Yang, M., Sharma, A. & Dreyfuss, G. Numerous microRNPs in neuronal cells containing novel microRNAs. RNA 9, 180–186 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Zeng, Y. & Cullen, B. R. Sequence requirements for micro RNA processing and function in human cells. RNA 9, 112–123 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Lund, E., Guttinger, S., Calado, A., Dahlberg, J. E. & Kutay, U. Nuclear export of microRNA precursors. Science 303, 95–98 (2004).

    CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. Ketting, R. F. et al. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 15, 2654–2659 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain. Nature 426, 465–469 (2003).

    CAS  PubMed  Google Scholar 

  58. Song, J. J. et al. The crystal structure of the Argonaute2 PAZ domain reveals an RNA binding motif in RNAi effector complexes. Nature Struct. Biol. 10, 1026–1032 (2003).

    CAS  PubMed  Google Scholar 

  59. Yan, K. S. et al. Structure and conserved RNA binding of the PAZ domain. Nature 426, 468–474 (2003).

    PubMed  Google Scholar 

  60. Carmell, M. A. & Hannon, G. J. RNase III enzymes and the initiation of gene silencing. Nature Struct. Mol. Biol. 11, 214–218 (2004).

    CAS  Google Scholar 

  61. Blaszczyk, J. et al. Crystallographic and modeling studies of RNase III suggest a mechanism for double-stranded RNA cleavage. Structure (Camb). 9, 1225–1236 (2001).

    CAS  Google Scholar 

  62. Papp, I. et al. Evidence for nuclear processing of plant micro RNA and short interfering RNA precursors. Plant Physiol. 132, 1382–1390 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Park, W., Li, J., Song, R., Messing, J. & Chen, X. CARPEL FACTORY, a Dicer homolog, and HEN1, a novel protein, act in microRNA metabolism in Arabidopsis thaliana. Curr. Biol. 12, 1484–1495 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Timmons, L. The long and short of siRNAs. Mol. Cell 10, 435–437 (2002).

    CAS  PubMed  Google Scholar 

  65. Schauer, S. E., Jacobsen, S. E., Meinke, D. W. & Ray, A. DICER-LIKE1: blind men and elephants in Arabidopsis development. Trends Plant Sci. 7, 487–491 (2002).

    CAS  PubMed  Google Scholar 

  66. Pham, J. W., Pellino, J. L., Lee, Y. S., Carthew, R. W. & Sontheimer, E. J. A Dicer-2-dependent 80S complex cleaves targeted mRNAs during RNAi in Drosophila. Cell 117, 83–94 (2004).

    CAS  PubMed  Google Scholar 

  67. 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).

    CAS  PubMed  Google Scholar 

  68. Jin, P. et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neurosci. 7, 113–117 (2004).

    CAS  PubMed  Google Scholar 

  69. Liu, Q. et al. R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway. Science 301, 1921–1925 (2003).

    CAS  PubMed  Google Scholar 

  70. Pellino, J. L. & Sontheimer, E. J. R2D2 leads the silencing trigger to mRNA's death star. Cell 115, 132–133 (2003).

    CAS  PubMed  Google Scholar 

  71. Schwarz, D. S. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199–208 (2003).

    CAS  PubMed  Google Scholar 

  72. Khvorova, A., Reynolds, A. & Jayasena, S. D. Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209–216 (2003). This paper, together with reference 71, characterized the regulatory mechanism of the asymmetric assembly of siRNA/miRNA into the RISC complex.

    CAS  PubMed  Google Scholar 

  73. 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  PubMed  Google Scholar 

  74. Hake, S. MicroRNAs: a role in plant development. Curr. Biol. 13, R851–R852 (2003).

    CAS  PubMed  Google Scholar 

  75. Carmell, M. A., Xuan, Z., Zhang, M. Q. & Hannon, G. J. The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev. 16, 2733–2742 (2002).

    CAS  PubMed  Google Scholar 

  76. Caudy, A. A. et al. A micrococcal nuclease homologue in RNAi effector complexes. Nature 425, 411–414 (2003).

    CAS  PubMed  Google Scholar 

  77. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  79. Lee, R. C. & Ambros, V. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862–864 (2001). This paper, together with references 77 and 78, was among the first cloning efforts to identify large numbers of miRNAs from worm, fly and mammals.

    CAS  PubMed  Google Scholar 

  80. Kim, J. et al. Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc. Natl Acad. Sci. USA 101, 360–365 (2004).

    CAS  PubMed  Google Scholar 

  81. Griffiths-Jones, S. The microRNA Registry. Nucleic Acids Res. 32 (Database issue), D109–D111 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 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  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  87. Aravin, A. A. et al. The small RNA profile during Drosophila melanogaster development. Dev. Cell 5, 337–350 (2003).

    CAS  PubMed  Google Scholar 

  88. Metzler, M., Wilda, M., Busch, K., Viehmann, S. & Borkhardt, A. High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39, 167–169 (2004).

    CAS  PubMed  Google Scholar 

  89. Calin, G. A. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl Acad. Sci. USA 101, 2999–3004 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Krichevsky, A. M., King, K. S., Donahue, C. P., Khrapko, K. & Kosik, K. S. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9, 1274–1281 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Knight, S. W. & Bass, B. L. A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science 293, 2269–2271 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Wienholds, E., Koudijs, M. J., van Eeden, F. J., Cuppen, E. & Plasterk, R. H. The microRNA-producing enzyme Dicer1 is essential for zebrafish development. Nature Genet. 35, 217–218 (2003).

    CAS  PubMed  Google Scholar 

  93. Bernstein, E. et al. Dicer is essential for mouse development. Nature Genet. 35, 215–217 (2003).

    CAS  PubMed  Google Scholar 

  94. Moussian, B., Schoof, H., Haecker, A., Jurgens, G. & Laux, T. Role of the ZWILLE gene in the regulation of central shoot meristem cell fate during Arabidopsis embryogenesis. EMBO J. 17, 1799–1809 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Cox, D. N. et al. A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes Dev. 12, 3715–3727 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 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 

  97. 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  PubMed  Google Scholar 

  98. Palatnik, J. F. et al. Control of leaf morphogenesis by microRNAs. Nature 425, 257–263 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  100. 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).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  102. Calin, G. A. et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 99, 15524–15529 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Michael, M. Z., O'Connor, S. M., van Holst Pellekaan, N. G., Young, G. P. & James, R. J. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol. Cancer Res. 1, 882–891 (2003).

    CAS  PubMed  Google Scholar 

  104. 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  PubMed  PubMed Central  Google Scholar 

  105. Emery, J. F. et al. Radial patterning of Arabidopsis shoots by class III HD-ZIP and KANADI genes. Curr. Biol. 13, 1768–1774 (2003).

    CAS  PubMed  Google Scholar 

  106. Juarez, M. T., Kui, J. S., Thomas, J., Heller, B. A. & Timmermans, M. C. microRNA-mediated repression of rolled leaf1 specifies maize leaf polarity. Nature 428, 84–88 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. M. Silva, A. M. Denli, L. E. Palmer, J. Liu, P. J. Paddison and E. P. Murchson for stimulating discussions and helpful input. We also thank J. C. Duffy for help with the figures. We are particularly grateful to M. A. Carmell and Z. Xuan, who provided valuable comments and suggestions in the preparation of this manuscript. G.J.H. is supported by an Innovator Award from the US Army Breast Cancer Research Program and by grants from the National Institutes of Health. L.H. is a Helen Hay Whitney Fellow.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gregory J. Hannon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

AP2

cog-1

hbl-1 (lin-57)

Hoxb8

let-7

lin-4

lin-14

lin-28

lin-41

lys-6

miR-9

miR-99a

miR-155

miR-181

miR-196

TAIR

DCL1

DCL2

DCL3

FURTHER INFORMATION

miRNA Registry

PHYLIP programs

Glossary

RNA INTERFERENCE

(RNAi). A form of post-transcriptional gene silencing, in which dsRNA induces degradation of the homologous mRNA, mimicking the effect of the reduction, or loss, of gene activity.

BOOTSTRAP SAMPLING

As applied to molecular phylogenies, nucleotide or amino-acid sites are sampled randomly, with replacement, and a new tree is constructed. This is repeated many times and the frequency of appearance of a particular node among the bootstrap trees is viewed as a support (confidence) value for deciding on the significance of that node.

S2 CELL

A cell line that is isolated from dissociated Drosophila melanogaster embryos. The cell line is phagocytic, which might contribute to its susceptibility to RNAi.

POLYSOME

A functional unit of protein synthesis that consists of several ribosomes that are attached along the length of a single molecule of mRNA.

MERISTEM

The undifferentiated tissue at the tips of stems and roots in which new cell division is concentrated.

P-ELEMENTS

A family of transposable elements that are widely used as the basis of tools for mutating and manipulating the Drosophila genome.

WING DISC

A sac-like structure of a mature third instar fly larva, which will give rise to the adult wing.

INFLORESCENCE TISSUE

The reproductive backbone that displays the flowers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, L., Hannon, G. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522–531 (2004). https://doi.org/10.1038/nrg1379

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1379

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