NeuroMolecular Medicine

, Volume 11, Issue 3, pp 162–172 | Cite as

microRNAs in CNS Disorders

  • Jannet Kocerha
  • Sakari Kauppinen
  • Claes Wahlestedt
Original Paper

Abstract

In recent years, there has been a shift in the conventional paradigms for transcriptional and translational regulation as extensive sequencing efforts have yielded new insights into the landscape of the human genome and transcriptome. Hundreds of non-coding regulatory RNA molecules called microRNAs (miRNAs) have been identified in the mammalian central nervous system (CNS) and are reported to mediate pivotal roles in many aspects of neuronal functions. Disruption of miRNA-based post-transcriptional regulation has been implicated in a range of CNS disorders as one miRNA is predicted to impact the expression of numerous downstream mRNA targets. The intricate molecular networks mediated by an miRNA form a robust mechanism for rapid and potent responses to cellular events throughout the development of the human brain. Recent studies have identified a molecular and ultimately pathogenic role for a subset of miRNAs in Alzheimer’s disease and schizophrenia, including the characterization of their downstream CNS mRNA targets, such as beta-secretase (BACE1) and calmodulin-dependent protein kinase II (CaMKII). Here, we present an overview of the current progress in miRNA research related to CNS disorders and also highlight the utility of LNA (locked nucleic acid)-modified oligonucleotides in the detection and modulation of miRNA activity.

Keywords

microRNA CNS Schizophrenia Alzheimer’s LNA 

References

  1. Abelson, J. F., Kwan, K. Y., O’Roak, B. J., Baek, D. Y., Stillman, A. A., Morgan, T. M., et al. (2005). Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science, 310, 317–320. doi: 10.1126/science.1116502.CrossRefPubMedGoogle Scholar
  2. Abu-Elneel, K., Liu, T., Gazzaniga, F. S., Nishimura, Y., Wall, D. P., Geschwind, D. H., et al. (2008). Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics, 9, 153–161. doi: 10.1007/s10048-008-0133-5.CrossRefPubMedGoogle Scholar
  3. Babiloni, C., Frisoni, G. B., Pievani, M., Vecchio, F., Lizio, R., Buttiglione, M., et al. (2009). Hippocampal volume and cortical sources of EEG alpha rhythms in mild cognitive impairment and Alzheimer disease. Neuroimage, 44, 123–135. doi: 10.1016/j.neuroimage.2008.08.005.CrossRefPubMedGoogle Scholar
  4. Bak, M., Silahtaroglu, A., Moller, M., Christensen, M., Rath, M. F., Skryabin, B., et al. (2008). MicroRNA expression in the adult mouse central nervous system. RNA, 14, 432–444. doi: 10.1261/rna.783108.CrossRefPubMedGoogle Scholar
  5. Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., et al. (2006). Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature, 442, 916–919. doi: 10.1038/nature05016.CrossRefPubMedGoogle Scholar
  6. Bartel, D. P. (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136, 215–233. doi: 10.1016/j.cell.2009.01.002.CrossRefPubMedGoogle Scholar
  7. Beveridge, N. J., Tooney, P. A., Carroll, A. P., Gardiner, E., Bowden, N., Scott, R. J., et al. (2008). Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Human Molecular Genetics, 17, 1156–1168. doi: 10.1093/hmg/ddn005.CrossRefPubMedGoogle Scholar
  8. Birney, E., Stamatoyannopoulos, J. A., Dutta, A., Guigo, R., Gingeras, T. R., Margulies, E. H., et al. (2007). Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature, 447, 799–816. doi: 10.1038/nature05874.CrossRefPubMedGoogle Scholar
  9. Boissonneault, V., Plante, I., Rivest, S., & Provost, P. (2009). MicroRNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-converting enzyme 1. Journal of Biological Chemistry, 284, 1971–1981. doi: 10.1074/jbc.M807530200.CrossRefPubMedGoogle Scholar
  10. Cao, X., Yeo, G., Muotri, A. R., Kuwabara, T., & Gage, F. H. (2006). Noncoding RNAs in the mammalian central nervous system. Annual Review of Neuroscience, 29, 77–103. doi: 10.1146/annurev.neuro.29.051605.112839.CrossRefPubMedGoogle Scholar
  11. Carninci, P., Kasukawa, T., Katayama, S., Gough, J., Frith, M. C., Maeda, N., et al. (2005). The transcriptional landscape of the mammalian genome. Science, 309, 1559–1563. doi: 10.1126/science.1112014.CrossRefPubMedGoogle Scholar
  12. Castoldi, M., Benes, V., Hentze, M. W., & Muckenthaler, M. U. (2007). miChip: A microarray platform for expression profiling of microRNAs based on locked nucleic acid (LNA) oligonucleotide capture probes. Methods, 43, 146–152. doi: 10.1016/j.ymeth.2007.04.009.CrossRefPubMedGoogle Scholar
  13. Castoldi, M., Schmidt, S., Benes, V., Hentze, M. W., & Muckenthaler, M. U. (2008). miChip: An array-based method for microRNA expression profiling using locked nucleic acid capture probes. Nature Protocols, 3, 321–329. doi: 10.1038/nprot.2008.4.CrossRefPubMedGoogle Scholar
  14. Castoldi, M., Schmidt, S., Benes, V., Noerholm, M., Kulozik, A. E., Hentze, M. W., et al. (2006). A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA). RNA, 12, 913–920. doi: 10.1261/rna.2332406.CrossRefPubMedGoogle Scholar
  15. Corominas, M., Roncero, C., Ribases, M., Castells, X., & Casas, M. (2007). Brain-derived neurotrophic factor and its intracellular signaling pathways in cocaine addiction. Neuropsychobiology, 55, 2–13. doi: 10.1159/000103570.CrossRefPubMedGoogle Scholar
  16. Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., et al. (2006). Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature, 442, 920–924. doi: 10.1038/nature05017.CrossRefPubMedGoogle Scholar
  17. Cui, Q., Yu, Z., Pan, Y., Purisima, E. O., & Wang, E. (2007). MicroRNAs preferentially target the genes with high transcriptional regulation complexity. Biochemical and Biophysical Research Communications, 352, 733–738. doi: 10.1016/j.bbrc.2006.11.080.CrossRefPubMedGoogle Scholar
  18. Cui, Q., Yu, Z., Purisima, E. O., & Wang, E. (2006). Principles of microRNA regulation of a human cellular signaling network. Molecular Systems Biology, 2, 46. doi: 10.1038/msb4100089.CrossRefPubMedGoogle Scholar
  19. Davis, T. H., Cuellar, T. L., Koch, S. M., Barker, A. J., Harfe, B. D., McManus, M. T., et al. (2008). Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. Journal of Neuroscience, 28, 4322–4330. doi: 10.1523/JNEUROSCI.4815-07.2008.CrossRefPubMedGoogle Scholar
  20. Dogini, D. B., Ribeiro, P. A., Rocha, C., Pereira, T. C., & Lopes-Cendes, I. (2008). MicroRNA expression profile in murine central nervous system development. Journal of Molecular Neuroscience, 35, 331–337. doi: 10.1007/s12031-008-9068-4.CrossRefPubMedGoogle Scholar
  21. Donner, J., Pirkola, S., Silander, K., Kananen, L., Terwilliger, J. D., Lonnqvist, J., et al. (2008). An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders. Biological Psychiatry, 64, 672–680. doi: 10.1016/j.biopsych.2008.06.002.CrossRefPubMedGoogle Scholar
  22. Doran, J., & Strauss, W. M. (2007). Bio-informatic trends for the determination of miRNA-target interactions in mammals. DNA and Cell Biology, 26, 353–360. doi: 10.1089/dna.2006.0546.CrossRefPubMedGoogle Scholar
  23. Elmen, J., Lindow, M., Schutz, S., Lawrence, M., Petri, A., Obad, S., et al. (2008a). LNA-mediated microRNA silencing in non-human primates. Nature, 452, 896–899. doi: 10.1038/nature06783.CrossRefPubMedGoogle Scholar
  24. Elmen, J., Lindow, M., Silahtaroglu, A., Bak, M., Christensen, M., Lind-Thomsen, A., et al. (2008b). Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Research, 36, 1153–1162. doi: 10.1093/nar/gkm1113.CrossRefPubMedGoogle Scholar
  25. Frieden, M., & Orum, H. (2008). Locked nucleic acid holds promise in the treatment of cancer. Current Pharmaceutical Design, 14, 1138–1142. doi: 10.2174/138161208784246234.CrossRefPubMedGoogle Scholar
  26. Glinsky, G. V. (2008). An SNP-guided microRNA map of fifteen common human disorders identifies a consensus disease phenocode aiming at principal components of the nuclear import pathway. Cell Cycle, 7, 2570–2583.PubMedGoogle Scholar
  27. Golde, T. E., Dickson, D., & Hutton, M. (2006). Filling the gaps in the abeta cascade hypothesis of Alzheimer’s disease. Current Alzheimer Research, 3, 421–430. doi: 10.2174/156720506779025189.CrossRefPubMedGoogle Scholar
  28. Grunweller, A., & Hartmann, R. K. (2007). Locked nucleic acid oligonucleotides: The next generation of antisense agents? BioDrugs, 21, 235–243. doi: 10.2165/00063030-200721040-00004.CrossRefPubMedGoogle Scholar
  29. Gustincich, S., Sandelin, A., Plessy, C., Katayama, S., Simone, R., Lazarevic, D., et al. (2006). The complexity of the mammalian transcriptome. Journal of Physiology, 575, 321–332. doi: 10.1113/jphysiol.2006.115568.CrossRefPubMedGoogle Scholar
  30. Hansen, T., Olsen, L., Lindow, M., Jakobsen, K. D., Ullum, H., Jonsson, E., et al. (2007). Brain expressed microRNAs implicated in schizophrenia etiology. PLoS ONE, 2, e873. doi: 10.1371/journal.pone.0000873.CrossRefPubMedGoogle Scholar
  31. Hebert, S. S., Horre, K., Nicolai, L., Papadopoulou, A. S., Mandemakers, W., Silahtaroglu, A. N., et al. (2008). Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proceedings of the National Academy of Sciences of the United States of America, 105, 6415–6420. doi: 10.1073/pnas.0710263105.CrossRefPubMedGoogle Scholar
  32. Jepsen, J. S., Sorensen, M. D., & Wengel, J. (2004). Locked nucleic acid: A potent nucleic acid analog in therapeutics and biotechnology. Oligonucleotides, 14, 130–146. doi: 10.1089/1545457041526317.CrossRefPubMedGoogle Scholar
  33. Johnson, R., Zuccato, C., Belyaev, N. D., Guest, D. J., Cattaneo, E., & Buckley, N. J. (2008). A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiology of Disease, 29, 438–445. doi: 10.1016/j.nbd.2007.11.001.CrossRefPubMedGoogle Scholar
  34. Kauppinen, S., Vester, B., & Wengel, J. (2006). Locked nucleic acid: High-affinity targeting of complementary RNA for RNomics. Handbook of Experimental Pharmacology, 405–422.Google Scholar
  35. Kaur, H., Babu, B. R., & Maiti, S. (2007). Perspectives on chemistry and therapeutic applications of Locked Nucleic Acid (LNA). Chemical Reviews, 107, 4672–4697. doi: 10.1021/cr050266u.CrossRefPubMedGoogle Scholar
  36. Ke, X. S., Liu, C. M., Liu, D. P., & Liang, C. C. (2003). MicroRNAs: Key participants in gene regulatory networks. Current Opinion in Chemical Biology, 7, 516–523. doi: 10.1016/S1367-5931(03)00075-9.CrossRefPubMedGoogle Scholar
  37. Kim, J., Inoue, K., Ishii, J., Vanti, W. B., Voronov, S. V., Murchison, E., et al. (2007). A MicroRNA feedback circuit in midbrain dopamine neurons. Science, 317, 1220–1224. doi: 10.1126/science.1140481.CrossRefPubMedGoogle Scholar
  38. Kloosterman, W. P., Wienholds, E., de Bruijn, E., Kauppinen, S., & Plasterk, R. H. (2006). In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes. Nature Methods, 3, 27–29. doi: 10.1038/nmeth843.CrossRefPubMedGoogle Scholar
  39. Kocerha, J., Faghihi, M. A., Lopez-Toledano, M. A., Huang, J., Ramsey A. J., Caron, M. G., et al. (2009). MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proceedings of the National Academy of Sciences of the United States of America. Google Scholar
  40. Kruger, J., & Rehmsmeier, M. (2006). RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Research, 34, W451–W454. doi: 10.1093/nar/gkl243.CrossRefPubMedGoogle Scholar
  41. Kye, M. J., Liu, T., Levy, S. F., Xu, N. L., Groves, B. B., Bonneau, R., et al. (2007). Somatodendritic microRNAs identified by laser capture and multiplex RT-PCR. RNA, 13, 1224–1234. doi: 10.1261/rna.480407.CrossRefPubMedGoogle Scholar
  42. Lau, P., Verrier, J. D., Nielsen, J. A., Johnson, K. R., Notterpek, L., & Hudson, L. D. (2008). Identification of dynamically regulated microRNA and mRNA networks in developing oligodendrocytes. Journal of Neuroscience, 28, 11720–11730. doi: 10.1523/JNEUROSCI.1932-08.2008.CrossRefPubMedGoogle Scholar
  43. Lugli, G., Torvik, V. I., Larson, J., & Smalheiser, N. R. (2008). Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain. Journal of Neurochemistry, 106, 650–661. doi: 10.1111/j.1471-4159.2008.05413.x.CrossRefPubMedGoogle Scholar
  44. Lukiw, W. J. (2007). Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. NeuroReport, 18, 297–300. doi: 10.1097/WNR.0b013e3280148e8b.CrossRefPubMedGoogle Scholar
  45. Lukiw, W. J., Zhao, Y., & Cui, J. G. (2008). An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. Journal of Biological Chemistry, 283, 31315–31322. doi: 10.1074/jbc.M805371200.CrossRefPubMedGoogle Scholar
  46. Mattick, J. S. (2001). Non-coding RNAs: The architects of eukaryotic complexity. EMBO Reports, 2, 986–991. doi: 10.1093/embo-reports/kve230.CrossRefPubMedGoogle Scholar
  47. Mattick, J. S., & Makunin, I. V. (2005). Small regulatory RNAs in mammals. Human Molecular Genetics, 14 Spec No 1:R121–R132.Google Scholar
  48. Mellios, N., Huang, H. S., Grigorenko, A., Rogaev, E., & Akbarian, S. (2008). A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Human Molecular Genetics, 17, 3030–3042. doi: 10.1093/hmg/ddn201.CrossRefPubMedGoogle Scholar
  49. Michelson, A. M. (2008). Developmental biology. From genetic association to genetic switch. Science, 322, 1803–1804. doi: 10.1126/science.1169216.CrossRefPubMedGoogle Scholar
  50. Miranda, K. C., Huynh, T., Tay, Y., Ang, Y. S., Tam, W. L., Thomson, A. M., et al. (2006). A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell, 126, 1203–1217. doi: 10.1016/j.cell.2006.07.031.CrossRefPubMedGoogle Scholar
  51. Mohn, A. R., Gainetdinov, R. R., Caron, M. G., & Koller, B. H. (1999). Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell, 98, 427–436. doi: 10.1016/S0092-8674(00)81972-8.CrossRefPubMedGoogle Scholar
  52. Nelson, P. T., Baldwin, D. A., Kloosterman, W. P., Kauppinen, S., Plasterk, R. H., & Mourelatos, Z. (2006). RAKE and LNA-ISH reveal microRNA expression and localization in archival human brain. RNA, 12, 187–191. doi: 10.1261/rna.2258506.CrossRefPubMedGoogle Scholar
  53. Orom, U. A., Kauppinen, S., & Lund, A. H. (2006). LNA-modified oligonucleotides mediate specific inhibition of microRNA function. Gene, 372, 137–141. doi: 10.1016/j.gene.2005.12.031.CrossRefPubMedGoogle Scholar
  54. Packer, A. N., Xing, Y., Harper, S. Q., Jones, L., & Davidson, B. L. (2008). The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. Journal of Neuroscience, 28, 14341–14346. doi: 10.1523/JNEUROSCI.2390-08.2008.CrossRefPubMedGoogle Scholar
  55. Papadopoulos, G. L., Reczko, M., Simossis, V. A., Sethupathy, P., & Hatzigeorgiou, A. G. (2009). The database of experimentally supported targets: A functional update of TarBase. Nucleic Acids Research, 37, D155–D158. doi: 10.1093/nar/gkn809.CrossRefPubMedGoogle Scholar
  56. Perkins, D. O., Jeffries, C. D., Jarskog, L. F., Thomson, J. M., Woods, K., Newman, M. A., et al. (2007). microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biology, 8, R27. doi: 10.1186/gb-2007-8-2-r27.CrossRefPubMedGoogle Scholar
  57. Rademakers, R., Eriksen, J. L., Baker, M., Robinson, T., Ahmed, Z., Lincoln, S. J., et al. (2008). Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Human Molecular Genetics, 17, 3631–3642. doi: 10.1093/hmg/ddn257.CrossRefPubMedGoogle Scholar
  58. Rosas, H. D., Salat, D. H., Lee, S. Y., Zaleta, A. K., Hevelone, N., & Hersch, S. M. (2008). Complexity and heterogeneity: What drives the ever-changing brain in Huntington’s disease? Annals of the New York Academy of Sciences, 1147, 196–205.PubMedCrossRefGoogle Scholar
  59. Sastre, M., Walter, J., & Gentleman, S. M. (2008). Interactions between APP secretases and inflammatory mediators. Journal of Neuroinflammation, 5, 25. doi: 10.1186/1742-2094-5-25.CrossRefPubMedGoogle Scholar
  60. Schratt, G. M., Tuebing, F., Nigh, E. A., Kane, C. G., Sabatini, M. E., Kiebler, M., et al. (2006). A brain-specific microRNA regulates dendritic spine development. Nature, 439, 283–289. doi: 10.1038/nature04367.CrossRefPubMedGoogle Scholar
  61. Silahtaroglu, A. N., Nolting, D., Dyrskjot, L., Berezikov, E., Moller, M., Tommerup, N., et al. (2007). Detection of microRNAs in frozen tissue sections by fluorescence in situ hybridization using locked nucleic acid probes and tyramide signal amplification. Nature Protocols, 2, 2520–2528. doi: 10.1038/nprot.2007.313.CrossRefPubMedGoogle Scholar
  62. Stark, K. L., Xu, B., Bagchi, A., Lai, W. S., Liu, H., Hsu, R., et al. (2008). Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nature Genetics, 40, 751–760. doi: 10.1038/ng.138.CrossRefPubMedGoogle Scholar
  63. Stenvang, J., Silahtaroglu, A. N., Lindow, M., Elmen, J., & Kauppinen, S. (2008). The utility of LNA in microRNA-based cancer diagnostics and therapeutics. Seminars in Cancer Biology, 18(2), 89–102.CrossRefPubMedGoogle Scholar
  64. Tapia-Arancibia, L., Aliaga, E., Silhol, M., & Arancibia, S. (2008). New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Research Reviews, 59, 201–220. doi: 10.1016/j.brainresrev.2008.07.007.CrossRefPubMedGoogle Scholar
  65. Thakker, D. R., Natt, F., Husken, D., Maier, R., Muller, M., van der Putten, H., et al. (2004). Neurochemical and behavioral consequences of widespread gene knockdown in the adult mouse brain by using nonviral RNA interference. Proceedings of the National Academy of Sciences of the United States of America, 101, 17270–17275. doi: 10.1073/pnas.0406214101.CrossRefPubMedGoogle Scholar
  66. Thakker, D. R., Natt, F., Husken, D., van der Putten, H., Maier, R., Hoyer, D., et al. (2005). siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain. Molecular Psychiatry, 10, 782–789, 714.Google Scholar
  67. Thomann, P. A., Schlafer, C., Seidl, U., Santos, V. D., Essig, M., & Schroder, J. (2008). The cerebellum in mild cognitive impairment and Alzheimer’s disease—A structural MRI study. Journal of Psychiatric Research, 42, 1198–1202. doi: 10.1016/j.jpsychires.2007.12.002.CrossRefPubMedGoogle Scholar
  68. van der Walt, J. M., Noureddine, M. A., Kittappa, R., Hauser, M. A., Scott, W. K., McKay, R., et al. (2004). Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. American Journal of Human Genetics, 74, 1121–1127. doi: 10.1086/421052.CrossRefPubMedGoogle Scholar
  69. van Winkel, R., Stefanis, N. C., & Myin-Germeys, I. (2008). Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophrenia Bulletin, 34, 1095–1105. doi: 10.1093/schbul/sbn101.CrossRefPubMedGoogle Scholar
  70. Wahlestedt, C., Salmi, P., Good, L., Kela, J., Johnsson, T., Hokfelt, T., et al. (2000). Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proceedings of the National Academy of Sciences of the United States of America, 97, 5633–5638. doi: 10.1073/pnas.97.10.5633.CrossRefPubMedGoogle Scholar
  71. Wang, G., van der Walt, J. M., Mayhew, G., Li, Y. J., Zuchner, S., Scott, W. K., et al. (2008a). Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. American Journal of Human Genetics, 82, 283–289. doi: 10.1016/j.ajhg.2007.09.021.CrossRefPubMedGoogle Scholar
  72. Wang, W. X., Rajeev, B. W., Stromberg, A. J., Ren, N., Tang, G., Huang, Q., et al. (2008b). The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. Journal of Neuroscience, 28, 1213–1223. doi: 10.1523/JNEUROSCI.5065-07.2008.CrossRefPubMedGoogle Scholar
  73. Wayman, G. A., Lee, Y. S., Tokumitsu, H., Silva, A., & Soderling, T. R. (2008). Calmodulin-kinases: Modulators of neuronal development and plasticity. Neuron, 59, 914–931. doi: 10.1016/j.neuron.2008.08.021.CrossRefPubMedGoogle Scholar
  74. Winter, J., Jung, S., Keller, S., Gregory, R. I., & Diederichs, S. (2009). Many roads to maturity: microRNA biogenesis pathways and their regulation. Nature Cell Biology, 11, 228–234. doi: 10.1038/ncb0309-228.CrossRefPubMedGoogle Scholar
  75. Winterer, G., & Weinberger, D. R. (2004). Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends in Neurosciences, 27, 683–690. doi: 10.1016/j.tins.2004.08.002.CrossRefPubMedGoogle Scholar
  76. Zhang, R., & Su, B. (2008). MicroRNA regulation and the variability of human cortical gene expression. Nucleic Acids Research, 36, 4621–4628. doi: 10.1093/nar/gkn431.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Jannet Kocerha
    • 1
  • Sakari Kauppinen
    • 2
    • 3
  • Claes Wahlestedt
    • 1
  1. 1.Department of Molecular and Integrative NeurosciencesScripps Research InstituteJupiterUSA
  2. 2.Santaris PharmaHorsholmDenmark
  3. 3.Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome ResearchUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations