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Author (up) Andoh-Noda, T.; Akamatsu, W.; Miyake, K.; Matsumoto, T.; Yamaguchi, R.; Sanosaka, T.; Okada, Y.; Kobayashi, T.; Ohyama, M.; Nakashima, K.; Kurosawa, H.; Kubota, T.; Okano, H. url  doi
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  Title Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage Type Journal Article
  Year 2015 Publication Molecular Brain Abbreviated Journal Mol Brain  
  Volume 8 Issue Pages 31  
  Keywords Astrocytes/*pathology; *Cell Differentiation; Cell Line; *Cell Lineage; Child; DNA Methylation/genetics; Fibroblasts/metabolism/pathology; Glial Fibrillary Acidic Protein/genetics; Humans; Induced Pluripotent Stem Cells/pathology; Methyl-CpG-Binding Protein 2/genetics; Mosaicism; Multipotent Stem Cells/*pathology; Mutation/genetics; Neural Stem Cells/*pathology; Protein Binding; Rett Syndrome/*pathology; Twins, Monozygotic; X Chromosome Inactivation/genetics  
  Abstract BACKGROUND: Rett syndrome (RTT) is one of the most prevalent neurodevelopmental disorders in females, caused by de novo mutations in the X-linked methyl CpG-binding protein 2 gene, MECP2. Although abnormal regulation of neuronal genes due to mutant MeCP2 is thought to induce autistic behavior and impaired development in RTT patients, precise cellular mechanisms underlying the aberrant neural progression remain unclear. RESULTS: Two sets of isogenic pairs of either wild-type or mutant MECP2-expressing human induced pluripotent stem cell (hiPSC) lines were generated from a single pair of 10-year-old RTT-monozygotic (MZ) female twins. Mutant MeCP2-expressing hiPSC lines did not express detectable MeCP2 protein during any stage of differentiation. The lack of MeCP2 reflected altered gene expression patterns in differentiated neural cells rather than in undifferentiated hiPSCs, as assessed by microarray analysis. Furthermore, MeCP2 deficiency in the neural cell lineage increased astrocyte-specific differentiation from multipotent neural stem cells. Additionally, chromatin immunoprecipitation (ChIP) and bisulfite sequencing assays indicated that anomalous glial fibrillary acidic protein gene (GFAP) expression in the MeCP2-negative, differentiated neural cells resulted from the absence of MeCP2 binding to the GFAP gene. CONCLUSIONS: An isogenic RTT-hiPSC model demonstrated that MeCP2 participates in the differentiation of neural cells. Moreover, MeCP2 deficiency triggers perturbation of astrocytic gene expression, yielding accelerated astrocyte formation from RTT-hiPSC-derived neural stem cells. These findings are likely to shed new light on astrocytic abnormalities in RTT, and suggest that astrocytes, which are required for neuronal homeostasis and function, might be a new target of RTT therapy.  
  Address Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. hidokano@a2.keio.jp  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1756-6606 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:26012557; PMCID:PMC4446051 Approved no  
  Call Number refbase @ user @ Serial 16759  
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