MicroRNAs in brain function and disease

Open Access
Article

Abstract

MicroRNAs (miRNAs), a class of small, non-protein-coding transcripts about 21 nucleotides long, have recently entered center stage in the study of posttranscriptional gene regulation. They are now thought to be involved in the control of about one third of all protein-coding genes and play a role in the majority of cellular processes that have been studied. We focus on the role of the miRNA pathway in brain development, function, and disease by highlighting recent observations with respect to miRNA-mediated gene regulation in neuronal differentiation, synaptic plasticity, and the circadian clock. We also discuss the implications of these findings with respect to the involvement of miRNAs in the etiopathology of brain disorders and pinpoint the emerging therapeutic potential of miRNAs for the treatment of human diseases.

References and Recommended Reading

  1. 1.
    Lee RC, Feinbaum RL, Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993, 75:843–854.PubMedCrossRefGoogle Scholar
  2. 2.
    Reinhart BJ, Slack FJ, Basson M, et al.: The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000, 403:901–906.PubMedCrossRefGoogle Scholar
  3. 3.
    Pasquinelli AE, Reinhart BJ, Slack F, et al.: Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000, 408:86–89.PubMedCrossRefGoogle Scholar
  4. 4.
    Lee RC, Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science 2001, 294:862–864.PubMedCrossRefGoogle Scholar
  5. 5.
    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T: Identification of novel genes coding for small expressed RNAs. Science 2001, 294:853–858.PubMedCrossRefGoogle Scholar
  6. 6.
    Lau NC, Lim LP, Weinstein EG, Bartel DP: An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 2001, 294:858–862.PubMedCrossRefGoogle Scholar
  7. 7.
    Molnar A, Schwach F, Studholme DJ, et al.: miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii. Nature 2007, 447:1126–1129.PubMedCrossRefGoogle Scholar
  8. 8.
    Zhao T, Li G, Mi S, et al.: A complex system of small RNAs in the unicellular green alga Chlamydomonas reinhardtii. Genes Dev 2007, 21:1190–1203.PubMedCrossRefGoogle Scholar
  9. 9.
    Ruby JG, Jan C, Player C, et al.: Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 2006, 127:1193–1207.PubMedCrossRefGoogle Scholar
  10. 10.
    Berezikov E, Thuemmler F, van Laake LW, et al.: Diversity of microRNAs in human and chimpanzee brain. Nat Genet 2006, 38:1375–1377.PubMedCrossRefGoogle Scholar
  11. 11.
    Zeng Y, Cullen BR: Recognition and cleavage of primary microRNA transcripts. Methods Mol Biol 2006, 342:49–56.PubMedGoogle Scholar
  12. 12.
    Ruby JG, Jan CH, Bartel DP: Intronic microRNA precursors that bypass Drosha processing. Nature 2007, 448:83–86.PubMedCrossRefGoogle Scholar
  13. 13.
    Lund E, Guttinger S, Calado A, et al.: Nuclear export of microRNA precursors. Science 2004, 303:95–98.PubMedCrossRefGoogle Scholar
  14. 14.
    Ketting RF, Fischer SE, Bernstein E, et al.: Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev 2001, 15:2654–2659.PubMedCrossRefGoogle Scholar
  15. 15.
    Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004, 116:281–297.PubMedCrossRefGoogle Scholar
  16. 16.
    Jackson RJ, Standart N: How do microRNAs regulate gene expression? Sci STKE 2007, 2007:re1.PubMedCrossRefGoogle Scholar
  17. 17.
    Nilsen TW: Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet 2007, 23:243–249.PubMedCrossRefGoogle Scholar
  18. 18.
    Eulalio A, Rehwinkel J, Stricker M, et al.: Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing. Genes Dev 2007, 21:2558–2570.PubMedCrossRefGoogle Scholar
  19. 19.
    Vasudevan S, Tong Y, Steitz JA: Switching from repression to activation: microRNAs can up-regulate translation. Science 2007, 318:1931–1934.PubMedCrossRefGoogle Scholar
  20. 20.
    Doench JG, Sharp PA: Specificity of microRNA target selection in translational repression. Genes Dev 2004, 18:504–511.PubMedCrossRefGoogle Scholar
  21. 21.
    Brennecke J, Stark A, Russell RB, Cohen SM: Principles of microRNA-target recognition. PLoS Biol 2005, 3:e85.PubMedCrossRefGoogle Scholar
  22. 22.
    Lewis BP, Burge CB, Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120:15–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Kloosterman WP, Plasterk RH: The diverse functions of microRNAs in animal development and disease. Dev Cell 2006, 11:441–450.PubMedCrossRefGoogle Scholar
  24. 24.
    Cao X, Yeo G, Muotri AR, et al.: Noncoding RNAs in the mammalian central nervous system. Annu Rev Neurosci 2006, 29:77–103.PubMedCrossRefGoogle Scholar
  25. 25.
    Krichevsky AM: MicroRNA profiling: from dark matter to white matter, or identifying new players in neurobiology. Scientific World Journal 2007, 7:155–166.PubMedGoogle Scholar
  26. 26.
    Kataoka Y, Takeichi M, Uemura T: Developmental roles and molecular characterization of a Drosophila homologue of Arabidopsis Argonaute1, the founder of a novel gene superfamily. Genes Cells 2001, 6:313–325.PubMedCrossRefGoogle Scholar
  27. 27.
    Chopra VS, Mishra RK: “Mir”acles in hox gene regulation. Bioessays 2006, 28:445–448.PubMedCrossRefGoogle Scholar
  28. 28.
    Iimura T, Pourquie O: Hox genes in time and space during vertebrate body formation. Dev Growth Differ 2007, 49:265–275.PubMedGoogle Scholar
  29. 29.
    Giraldez AJ, Cinalli RM, Glasner ME, et al.: MicroRNAs regulate brain morphogenesis in zebrafish. Science 2005, 308:833–838.PubMedCrossRefGoogle Scholar
  30. 30.
    Chang S, Johnston RJ Jr, Frokjaer-Jensen C, et al.: MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode. Nature 2004, 430:785–789.PubMedCrossRefGoogle Scholar
  31. 31.
    Johnston RJ Jr, Chang S, Etchberger JF, et al.: MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proc Natl Acad Sci U S A 2005, 102:12449–12454.PubMedCrossRefGoogle Scholar
  32. 32.
    Johnston RJ, Hobert O: A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 2003, 426:845–849.PubMedCrossRefGoogle Scholar
  33. 33.
    Krichevsky AM, Sonntag KC, Isacson O, Kosik KS: Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 2006, 24:857–864.PubMedCrossRefGoogle Scholar
  34. 34.
    Lim LP, Lau NC, Garrett-Engele P, et al.: Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005, 433:769–773.PubMedCrossRefGoogle Scholar
  35. 35.
    Makeyev EV, Zhang J, Carrasco MA, Maniatis T: The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 2007, 27:435–448.PubMedCrossRefGoogle Scholar
  36. 36.
    Conaco C, Otto S, Han JJ, and Mandel G: Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A 2006, 103:2422–2427.PubMedCrossRefGoogle Scholar
  37. 37.
    Kim J, Inoue K, Ishii J, et al.: A MicroRNA feedback circuit in midbrain dopamine neurons. Science 2007, 317:1220–1224.PubMedCrossRefGoogle Scholar
  38. 38.
    Schaefer A, O’Carroll D, Tan CL, et al.: Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med 2007, 204:1553–1558.PubMedCrossRefGoogle Scholar
  39. 39.
    Hengst U, Cox LJ, Macosko EZ, Jaffrey SR: Functional and selective RNA interference in developing axons and growth cones. J Neurosci 2006, 26:5727–5732.PubMedCrossRefGoogle Scholar
  40. 40.
    Slack FJ, Weidhaas JB: MicroRNAs as a potential magic bullet in cancer. Future Oncol 2006, 2:73–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Sutton MA, Schuman EM: Dendritic protein synthesis, synaptic plasticity, and memory. Cell 2006, 127:49–58.PubMedCrossRefGoogle Scholar
  42. 42.
    Kang H, Schuman EM: A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 1996, 273:1402–1406.PubMedCrossRefGoogle Scholar
  43. 43.
    Huber KM, Kayser MS, Bear MF: Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 2000, 288:1254–1257.PubMedCrossRefGoogle Scholar
  44. 44.
    Huber KM, Roder JC, Bear MF: Chemical induction of mGluR5-and protein synthesis—dependent long-term depression in hippocampal area CA1. J Neurophysiol 2001, 86:321–325.PubMedGoogle Scholar
  45. 45.
    Aakalu G, Smith WB, Nguyen N, et al.: Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron 2001, 30:489–502.PubMedCrossRefGoogle Scholar
  46. 46.
    Kye MJ, Liu T, Levy SF, et al.: Somatodendritic microRNAs identified by laser capture and multiplex RT-PCR. RNA 2007, 13:1224–1234.PubMedCrossRefGoogle Scholar
  47. 47.
    Kosik KS: The neuronal microRNA system. Nat Rev Neurosci 2006, 7:911–920.PubMedCrossRefGoogle Scholar
  48. 48.
    Lamont EW, Legault-Coutu D, Cermakian N, Boivin DB: The role of circadian clock genes in mental disorders. Dialogues Clin Neurosci 2007, 9:333–342.PubMedGoogle Scholar
  49. 49.
    Cheng HY, Papp JW, Varlamova O, et al.: microRNA modulation of circadian-clock period and entrainment. Neuron 2007, 54:813–829.PubMedCrossRefGoogle Scholar
  50. 50.
    Cheng HY, Obrietan K: Revealing a role of microRNAs in the regulation of the biological clock. Cell Cycle 2007, 6:3034–3035.PubMedGoogle Scholar
  51. 51.
    Esquela-Kerscher A, Slack FJ: Oncomirs — microRNAs with a role in cancer. Nat Rev Cancer 2006, 6:259–269.PubMedCrossRefGoogle Scholar
  52. 52.
    Kent OA, Mendell JT: A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 2006, 25:6188–6196.PubMedCrossRefGoogle Scholar
  53. 53.
    O’Donnell WT, Warren ST: A decade of molecular studies of fragile X syndrome. Annu Rev Neurosci 2002, 25:315–338.PubMedCrossRefGoogle Scholar
  54. 54.
    Bardoni B, Mandel JL: Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. Curr Opin Genet Dev 2002, 12:284–293.PubMedCrossRefGoogle Scholar
  55. 55.
    Jin P, Alisch RS, Warren ST: RNA and microRNAs in fragile X mental retardation. Nat Cell Biol 2004, 6:1048–1053.PubMedCrossRefGoogle Scholar
  56. 56.
    Jin P, Zarnescu DC, Ceman S, et al.: Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat Neurosci 2004, 7:113–117.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen W, Jensen LR, Gecz J, et al.: Mutation screening of brain-expressed X-chromosomal miRNA genes in 464 patients with nonsyndromic X-linked mental retardation. Eur J Hum Genet 2007, 15:375–378.PubMedCrossRefGoogle Scholar
  58. 58.
    Zhang L, Wang T, Wright AF, et al.: A microdeletion in Xp11.3 accounts for co-segregation of retinitis pigmentosa and mental retardation in a large kindred. Am J Med Genet A 2006, 140:349–357.PubMedGoogle Scholar
  59. 59.
    Abelson JF, Kwan KY, O’Roak BJ, et al.: Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science 2005, 310:317–320.PubMedCrossRefGoogle Scholar
  60. 60.
    Johnson R, Zuccato C, Belyaev ND, et al.: A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiol Dis 2008, 29:438–445.PubMedCrossRefGoogle Scholar
  61. 61.
    Zuccato C, Tartari M, Crotti A, et al.: Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 2003, 35:76–83.PubMedCrossRefGoogle Scholar
  62. 62.
    Regier DA, Narrow WE, Rae DS, et al.: The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry 1993, 50:85–94.PubMedGoogle Scholar
  63. 63.
    Perkins DO, Jeffries CD, Jarskog LF, et al.: microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 2007, 8:R27.PubMedCrossRefGoogle Scholar
  64. 64.
    Krutzfeldt J, Rajewsky N, Braich R, et al.: Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005, 438:685–689.PubMedCrossRefGoogle Scholar
  65. 65.
    Krutzfeldt J, Kuwajima S, Braich R, et al.: Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res 2007, 35:2885–2892.PubMedCrossRefGoogle Scholar
  66. 66.
    Ebert MS, Neilson JR, Sharp PA: MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007, 4:721–726.PubMedCrossRefGoogle Scholar
  67. 67.
    Bumcrot D, Manoharan M, Koteliansky V, Sah DW: RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2006, 2:711–719.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Department for Human Molecular GeneticsMax Planck Institute for Molecular GeneticsBerlinGermany

Personalised recommendations