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The Role of Noncoding RNAs in Neurodevelopmental Disorders: The Case of Rett Syndrome

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Neuroepigenomics in Aging and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((PMISB,volume 978))

Abstract

Current technologies have demonstrated that only a small fraction of our genes encode for protein products. The vast majority of the human transcriptome corresponds to noncoding RNA (ncRNA) of different size, localization, and expression profile. Despite the fact that a biological function remains yet to be determined for most ncRNAs, growing evidence points to their crucial regulatory roles at all stages in gene expression regulation, including transcriptional and posttranscriptional control, so that proper cell homeostasis seems to depend largely on a variety of ncRNA-mediated regulatory networks. This is particularly relevant in the human brain, which displays the richest repertoire of ncRNA species, and where several different ncRNA molecules are known to be involved in crucial steps for brain development and maturation. Rett syndrome is a neurodevelopmental disorder characterized by loss of function mutations in the X-linked gene encoding for methyl-CpG-binding protein 2 (MeCP2). MECP2 deficiency impacts globally on gene expression programs, mainly through its role as a transcriptional repressor, and growing data also points to an important dysregulation of the noncoding transcriptome in the disease. Here, we review the current knowledge on ncRNA alterations in Rett and explore links with other pathologies that might indicate the potential use of particular noncoding transcripts as therapeutical targets, tools, or disease biomarkers.

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References

  1. Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, et al. Ensembl 2013. Nucleic Acids Res. 2013;41:D48–55.

    Article  CAS  PubMed  Google Scholar 

  2. Qureshi IA, Mehler MF. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci. 2012;13:528–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mills JD, Chen BJ, Ueberham U, Arendt T, Janitz M. The antisense transcriptome and the human brain. J Mol Neurosci. 2016;58:1–15.

    Article  CAS  PubMed  Google Scholar 

  4. Moazed D. Small RNAs in transcriptional gene silencing and genome defence. Nature. 2009;457:413–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Guil S, Esteller M. RNA–RNA interactions in gene regulation: the coding and noncoding players. Trends Biochem Sci. 2015;40:248–56.

    Article  CAS  PubMed  Google Scholar 

  6. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22:1775–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Washietl S, Kellis M, Garber M. Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals. Genome Res. 2014;24:616–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chodroff RA, Goodstadt L, Sirey TM, Oliver PL, Davies KE, Green ED, et al. Long noncoding RNA genes: conservation of sequence and brain expression among diverse amniotes. Genome Biol. 2010;11:R72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. He Z, Bammann H, Han D, Xie G, Khaitovich P. Conserved expression of lincRNA during human and macaque prefrontal cortex development and maturation. RNA. 2014;20:1103–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Briggs JA, Wolvetang EJ, Mattick JS, Rinn JL, Barry G. Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron. 2015;88:861–77.

    Article  CAS  PubMed  Google Scholar 

  11. Aprea J, Calegari F. Long non-coding RNAs in corticogenesis: deciphering the non-coding code of the brain. EMBO J. 2015;34:2865–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bortolin-Cavaille ML, Cavaille J. The SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters at the imprinted Prader-Willi locus generate canonical box C/D snoRNAs. Nucleic Acids Res. 2012;40:6800–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alders M, Blie J, vd Lip K, vd Bogaard R, Mannens M. Determination of KCNQ1OT1 and H19 methylation levels in BWS and SRS patients using methylation-sensitive high-resolution melting analysis. Eur J Hum Genet. 2009;17:467–73.

    Article  CAS  PubMed  Google Scholar 

  14. Chen I, Chen CY, Chuang TJ. Biogenesis, identification, and function of exonic circular RNAs. Wiley Interdiscip Rev RNA. 2015;6:563–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.

    Article  CAS  PubMed  Google Scholar 

  16. Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56:55–66.

    Article  CAS  PubMed  Google Scholar 

  17. Guo JU, Agarwal V, Guo H, Bartel DP. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15:409.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell. 2015;58:870–85.

    Article  CAS  PubMed  Google Scholar 

  19. Venø MT, Hansen TB, Venø ST, Clausen BH, Grebing M, Finsen B, et al. Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol. 2015;16:245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Lukiw WJ. Circular RNA (circRNA) in Alzheimer’s disease (AD). Front Genet. 2015;4:307.

    Google Scholar 

  21. Rett A. On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien Med Wochenschr. 1966;116:723–6.

    CAS  PubMed  Google Scholar 

  22. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–8.

    Article  CAS  PubMed  Google Scholar 

  23. Weng SM, Bailey ME, Cobb SR. Rett syndrome: from bed to bench. Pediatr Neonatol. 2011;52:309–16.

    Article  PubMed  Google Scholar 

  24. Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56:422–37.

    Article  CAS  PubMed  Google Scholar 

  25. Balachandar V, Dhivya V, Gomathi M, Mohanadevi S, Venkatesh B, Geetha B. A review of Rett syndrome (RTT) with induced pluripotent stem cells. Stem Cell Invest. 2016;3:52.

    Article  CAS  Google Scholar 

  26. Castro J, Mellios N, Sur M. Mechanisms and therapeutic challenges in autism spectrum disorders: insights from Rett syndrome. Curr Opin Neurol. 2013;26:154–9.

    Article  CAS  PubMed  Google Scholar 

  27. Weese-Mayer DE, Lieske SP, Boothby CM, Kenny AS, Bennett HL, Silvestri JM, et al. Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome. Pediatr Res. 2006;60:443–9.

    Article  PubMed  Google Scholar 

  28. Kerr AM, Armstrong DD, Prescott RJ, Doyle D, Kearney DL. Rett syndrome: analysis of deaths in the British survey. Eur Child Adolesc Psychiatry. 1997;6(Suppl 1):71–4.

    PubMed  Google Scholar 

  29. Katz DM, Bird A, Coenraads M, Gray SJ, Menon DU, Philpot BD, et al. Rett syndrome: crossing the threshold to clinical translation. Trends Neurosci. 2016;39:100–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lyst MJ, Bird A. Rett syndrome: a complex disorder with simple roots. Nat Rev Genet. 2015;16:261–75.

    Article  CAS  PubMed  Google Scholar 

  31. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393:386–9.

    Article  CAS  PubMed  Google Scholar 

  32. Guy J, Cheval H, Selfridge J, Bird A. The role of MeCP2 in the brain. Annu Rev Cell Dev Biol. 2011;27:631–52.

    Article  CAS  PubMed  Google Scholar 

  33. Cheng TL, Wang Z, Liao Q, Zhu Y, Zhou WH, Xu W, et al. MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev Cell. 2014;28:547–60.

    Article  CAS  PubMed  Google Scholar 

  34. Itoh M, Tahimic CG, Ide S, Otsuki A, Sasaoka T, Noguchi S, et al. Methyl CpG-binding protein isoform MeCP2_e2 is dispensable for Rett syndrome phenotypes but essential for embryo viability and placenta development. J Biol Chem. 2012;287:13859–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jain D, Singh K, Chirumamilla S, Bibat GM, Blue ME, Naidu SR, et al. Ocular MECP2 protein expression in patients with and without Rett syndrome. Pediatr Neurol. 2010;43:35–40.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 2002;11:115–24.

    Article  CAS  PubMed  Google Scholar 

  37. Banerjee A, Castro J, Sur M. Rett syndrome: genes, synapses, circuits, and therapeutics. Front Psychiatry. 2012;3:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature. 2010;468:263–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, et al. A role for glia in the progression of Rett’s syndrome. Nature. 2011;475:497–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ehrhart F, Coort SL, Cirillo E, Smeets E, Evelo CT, Curfs LM. Rett syndrome—biological pathways leading from MECP2 to disorder phenotypes. Orphanet J Rare Dis. 2016;11:158.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Cuddapah VA, Pillai RB, Shekar KV, Lane JB, Motil KJ, Skinner SA, et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 2014;51:152–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tate P, Skarnes W, Bird A. The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nat Genet. 1996;12:205–8.

    Article  CAS  PubMed  Google Scholar 

  43. Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001;27:322–6.

    Article  CAS  PubMed  Google Scholar 

  44. Pelka GJ, Watson CM, Radziewic T, Hayward M, Lahooti H, Christodoulou J, et al. Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice. Brain. 2006;129:887–98.

    Article  PubMed  Google Scholar 

  45. Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001;27:327–31.

    Article  CAS  PubMed  Google Scholar 

  46. Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, et al. Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron. 2008;59:947–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Samaco RC, Mandel-Brehm C, Chao HT, Ward CS, Fyffe-Maricich SL, Ren J, et al. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc Natl Acad Sci U S A. 2009;106:21966–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Huang TW, Kochukov MY, Ward CS, Merritt J, Thomas K, Nguyen T, et al. Progressive changes in a distributed neural circuit underlie breathing abnormalities in mice lacking MeCP2. J Neurosci. 2016;36:5572–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chao HT, Zoghbi HY, Rosenmund C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron. 2007;56:58–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE, et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999;65:1520–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Katz DM, Berger-Sweeney JE, Eubanks JH, Justice MJ, Neul JL, Pozzo-Miller L, et al. Preclinical research in Rett syndrome: setting the foundation for translational success. Dis Model Mech. 2012;5:733–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tsuchiya Y, Minami Y, Umemura Y, Watanabe H, Ono D, Nakamura W, et al. Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse. Genes Cells. 2015;20:992–1005.

    Article  CAS  PubMed  Google Scholar 

  53. Paquet D, Kwart D, Chen A, Sproul A, Jacob S, Teo S, et al. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature. 2016;533:125–9.

    Article  CAS  PubMed  Google Scholar 

  54. Xue HY, Ji LJ, Gao AM, Liu P, He JD, Lu XJ. CRISPR-Cas9 for medical genetic screens: applications and future perspectives. J Med Genet. 2016;53:91–7.

    Article  CAS  PubMed  Google Scholar 

  55. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  CAS  PubMed  Google Scholar 

  56. Santostefano KE, Hamazaki T, Biel NM, Jin S, Umezawa A, Terada N. A practical guide to induced pluripotent stem cell research using patient samples. Lab Invest. 2015;95:4–13.

    Article  CAS  PubMed  Google Scholar 

  57. Russo FB, Cugola FR, Fernandes IR, Pignatari GC, Beltrao-Braga PC. Induced pluripotent stem cells for modeling neurological disorders. World J Transplant. 2015;5:209–21.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Cheung AY, Horvath LM, Grafodatskaya D, Pasceri P, Weksberg R, Hotta A, et al. Isolation of MECP2-null Rett syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet. 2011;20:2103–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hotta A, Cheung AY, Farra N, Garcha K, Chang WY, Pasceri P, et al. EOS lentiviral vector selection system for human induced pluripotent stem cells. Nat Protoc. 2009;4:1828–44.

    Article  CAS  PubMed  Google Scholar 

  60. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010;143:527–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tchieu J, Kuoy E, Chin MH, Trinh H, Patterson M, Sherman SP, et al. Female human iPSCs retain an inactive X chromosome. Cell Stem Cell. 2010;7:329–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bhatnagar S, Zhu X, Ou J, Lin L, Chamberlain L, Zhu LJ, et al. Genetic and pharmacological reactivation of the mammalian inactive X chromosome. Proc Natl Acad Sci U S A. 2014;111:12591–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell. 2013;152:1308–23.

    Article  CAS  PubMed  Google Scholar 

  64. Richard JL, Ogawa Y. Understanding the complex circuitry of lncRNAs at the X-inactivation center and its implications in disease conditions. Curr Top Microbiol Immunol. 2016;394:1–27.

    PubMed  Google Scholar 

  65. Vacca M, Della Ragione F, Scalabri F, D’Esposito M. X inactivation and reactivation in X-linked diseases. Semin Cell Dev Biol. 2016;56:78–87.

    Article  PubMed  Google Scholar 

  66. Fineberg SK, Kosik KS, Davidson BL. MicroRNAs potentiate neural development. Neuron. 2009;64:303–9.

    Article  CAS  PubMed  Google Scholar 

  67. Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT, et al. Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci. 2008;28:4322–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, et al. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439:283–9.

    Article  CAS  PubMed  Google Scholar 

  69. Kawase-Koga Y, Otaegi G, Sun T. Different timings of Dicer deletion affect neurogenesis and gliogenesis in the developing mouse central nervous system. Dev Dyn. 2009;238:2800–12.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Urdinguio RG, Fernandez AF, Lopez-Nieva P, Rossi S, Huertas D, Kulis M, et al. Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome. Epigenetics. 2010;5:656–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lyu JW, Yuan B, Cheng TL, Qiu ZL, Zhou WH. Reciprocal regulation of autism-related genes MeCP2 and PTEN via microRNAs. Sci Rep. 2016;6:20392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wu H, Tao J, Chen PJ, Shahab A, Ge W, Hart RP, et al. Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2010;107:18161–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nomura T, Kimura M, Horii T, Morita S, Soejima H, Kudo S, et al. MeCP2-dependent repression of an imprinted miR-184 released by depolarization. Hum Mol Genet. 2008;17:1192–9.

    Article  CAS  PubMed  Google Scholar 

  74. Ben-Shachar S, Chahrour M, Thaller C, Shaw CA, Zoghbi HY. Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. Hum Mol Genet. 2009;18:2431–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320:1224–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li W, Pozzo-Miller L. BDNF deregulation in Rett syndrome. Neuropharmacology. 2014;76 Pt C:737–46.

    Article  PubMed  CAS  Google Scholar 

  77. Bebbington A, Percy A, Christodoulou J, Ravine D, Ho G, Jacoby P, et al. Updating the profile of C-terminal MECP2 deletions in Rett syndrome. J Med Genet. 2010;47:242–8.

    Article  CAS  PubMed  Google Scholar 

  78. Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M, et al. miR-199a links MeCP2 with mTOR signaling and its dysregulation leads to Rett syndrome phenotypes. Cell Rep. 2015;12:1887–901.

    Article  CAS  PubMed  Google Scholar 

  79. Buffington SA, Huang W, Costa-Mattioli M. Translational control in synaptic plasticity and cognitive dysfunction. Annu Rev Neurosci. 2014;37:17–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G, et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet. 2011;20:1182–96.

    Article  CAS  PubMed  Google Scholar 

  81. Li Y, Wang H, Muffat J, Cheng AW, Orlando DA, Lovén J, et al. Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons. Cell Stem Cell. 2013;13:446–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A. 2009;106:2029–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang Y, Chen M, Qiu Z, Hu K, McGee W, Chen X, et al. MiR-130a regulates neurite outgrowth and dendritic spine density by targeting MeCP2. Protein Cell. 2016;7:489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rodrigues DC, Kim DS, Yang G, Zaslavsky K, Ha KC, Mok RS, et al. MECP2 is post-transcriptionally regulated during human neurodevelopment by combinatorial action of RNA-binding proteins and miRNAs. Cell Rep. 2016;17:720–34.

    Article  CAS  PubMed  Google Scholar 

  85. Han K, Gennarino VA, Lee Y, Pang K, Hashimoto-Torii K, Choufani S, et al. Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev. 2013;27:485–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci. 2007;10:1513–4.

    Article  CAS  PubMed  Google Scholar 

  87. Alvarez-Saavedra M, Antoun G, Yanagiya A, Oliva-Hernandez R, Cornejo-Palma D, Perez-Iratxeta C, et al. miRNA-132 orchestrates chromatin remodeling and translational control of the circadian clock. Hum Mol Genet. 2011;20:731–51.

    Article  CAS  PubMed  Google Scholar 

  88. Chen Y, Shin BC, Thamotharan S, Devaskar SU. Differential methylation of the micro-RNA 7b gene targets postnatal maturation of murine neuronal Mecp2 gene expression. Dev Neurobiol. 2014;74:407–25.

    Article  CAS  PubMed  Google Scholar 

  89. Lin N, Chang KY, Li Z, Gates K, Rana ZA, Dang J, et al. An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment. Mol Cell. 2014;53:1005–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ng SY, Bogu GK, Soh BS, Stanton LW. The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell. 2013;51:349–59.

    Article  CAS  PubMed  Google Scholar 

  91. Mo CF, Wu FC, Tai KY, Chang WC, Chang KW, Kuo HC, et al. Loss of non-coding RNA expression from the DLK1-DIO3 imprinted locus correlates with reduced neural differentiation potential in human embryonic stem cell lines. Stem Cell Res Ther. 2015;6:1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. D’haene E, Jacobs EZ, Volders PJ, De Meyer T, Menten B, Vergult S. Identification of long non-coding RNAs involved in neuronal development and intellectual disability. Sci Rep. 2016;6:28396.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Petazzi P, Sandoval J, Szczesna K, Jorge OC, Roa L, Sayols S, et al. Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model. RNA Biol. 2013;10:1197–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Harvey VL, Duguid IC, Krasel C, Stephens GJ. Evidence that GABA rho subunits contribute to functional ionotropic GABA receptors in mouse cerebellar Purkinje cells. J Physiol. 2006;577:127–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Maxwell SS, Pelka GJ, Tam PP, El-Osta A. Chromatin context and ncRNA highlight targets of MeCP2 in brain. RNA Biol. 2013;10:1741–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bond AM, Vangompel MJ, Sametsky EA, Clark MF, Savage JC, Disterhoft JF, et al. Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat Neurosci. 2009;12:1020–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Berghoff EG, Clark MF, Chen S, Cajigas I, Leib DE, Kohtz JD. Evf2 (Dlx6as) lncRNA regulates ultraconserved enhancer methylation and the differential transcriptional control of adjacent genes. Development. 2013;140:4407–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, et al. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci. 2010;11:14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Sanuki R, Onishi A, Koike C, Muramatsu R, Watanabe S, Muranishi Y, et al. miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression. Nat Neurosci. 2011;14:1125–34.

    Article  CAS  PubMed  Google Scholar 

  100. Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP, et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol. 2012;30:453–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chang Q, Khare G, Dani V, Nelson S, Jaenisch R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron. 2006;49:341–8.

    Article  CAS  PubMed  Google Scholar 

  102. Kline DD, Ogier M, Kunze DL, Katz DM. Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice. J Neurosci. 2010;30:5303–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang Y, Zhao X, Ju W, Flory M, Zhong J, Jiang S, et al. Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder. Transl Psychiatry. 2015;5:e660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Guy J, Gan J, Selfridge J, Cobb S, Bird A. Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007;315:1143–7.

    Article  CAS  PubMed  Google Scholar 

  105. Huang HS, Allen JA, Mabb AM, King IF, Miriyala J, Taylor-Blake B, et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. 2011;481:185–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature. 2015;518:409–12.

    Article  CAS  PubMed  Google Scholar 

  107. Gray SJ, Matagne V, Bachaboina L, Yadav S, Ojeda SR, Samulski RJ. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther. 2011;19:1058–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gadalla KK, Bailey ME, Spike RC, Ross PD, Woodard KT, Kalburgi SN, et al. Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol Ther. 2013;21:18–30.

    Article  CAS  PubMed  Google Scholar 

  109. Deogracias R, Yazdani M, Dekkers MP, Guy J, Ionescu MC, Vogt KE, et al. Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2012;109:14230–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Johnson RA, Lam M, Punzo AM, Li H, Lin BR, Ye K, et al. 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J Appl Physiol. 1985;112:704–10.

    Article  CAS  Google Scholar 

  111. Kondo M, Gray LJ, Pelka GJ, Christodoulou J, Tam PP, Hannan AJ. Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome—Mecp2 gene dosage effects and BDNF expression. Eur J Neurosci. 2008;27:3342–50.

    Article  PubMed  Google Scholar 

  112. Larimore JL, Chapleau CA, Kudo S, Theibert A, Percy AK, Pozzo-Miller L. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol Dis. 2009;34:199–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ramirez JM, Ward CS, Neul JL. Breathing challenges in Rett syndrome: lessons learned from humans and animal models. Respir Physiol Neurobiol. 2013;189:280–7.

    Article  PubMed  Google Scholar 

  114. Hsiao J, Yuan TY, Tsai MS, Lu CY, Lin YC, Lee ML, et al. Upregulation of haploinsufficient gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of Dravet syndrome. EBioMedicine. 2016;9:257–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Ministerio de Economía y Competitividad (MINECO, grant number SAF2014-56894-R). A. O-G. is a recipient of a Predoctoral Research Grant from MINECO (file BES-2015-071452). We apologize to authors whose work could not be cited due to space constraints.

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  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain

    Aida Obiols-Guardia M.Sc. & Sònia Guil Ph.D.

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  1. Aida Obiols-Guardia M.Sc.
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  2. Sònia Guil Ph.D.
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Correspondence to Sònia Guil Ph.D. .

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  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), CATALONIA, Spain

    Raul Delgado-Morales

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Obiols-Guardia, A., Guil, S. (2017). The Role of Noncoding RNAs in Neurodevelopmental Disorders: The Case of Rett Syndrome. In: Delgado-Morales, R. (eds) Neuroepigenomics in Aging and Disease. Advances in Experimental Medicine and Biology(), vol 978. Springer, Cham. https://doi.org/10.1007/978-3-319-53889-1_2

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