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Analysis of induced pluripotent stem cells carrying 22q11.2 deletion.
Toyoshima, M; Akamatsu, W; Okada, Y; Ohnishi, T; Balan, S; Hisano, Y; Iwayama, Y; Toyota, T; Matsumoto, T; Itasaka, N; Sugiyama, S; Tanaka, M; Yano, M; Dean, B; Okano, H; Yoshikawa, T.
Affiliation
  • Toyoshima M; Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
  • Akamatsu W; Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
  • Okada Y; Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
  • Ohnishi T; Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
  • Balan S; Department of Neurology, School of Medicine, Aichi Medical University, Aichi, Japan.
  • Hisano Y; Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
  • Iwayama Y; Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
  • Toyota T; Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
  • Matsumoto T; Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
  • Itasaka N; Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
  • Sugiyama S; Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
  • Tanaka M; Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
  • Yano M; Laboratory of Protein Conformation Diseases, RIKEN Brain Science Institute, Saitama, Japan.
  • Dean B; Laboratory of Protein Conformation Diseases, RIKEN Brain Science Institute, Saitama, Japan.
  • Okano H; Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
  • Yoshikawa T; The Florey Institute of Neuroscience and Mental Health, Howard Florey Laboratories, The University of Melbourne, VIC, Australia.
Transl Psychiatry ; 6(11): e934, 2016 11 01.
Article in En | MEDLINE | ID: mdl-27801899
Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8, a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al., 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP, a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers (IL1B and IL6) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Pluripotent Stem Cells / 22q11 Deletion Syndrome Type of study: Observational_studies Limits: Adolescent / Adult / Female / Humans / Male Language: En Journal: Transl Psychiatry Year: 2016 Document type: Article Affiliation country: Japan Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Pluripotent Stem Cells / 22q11 Deletion Syndrome Type of study: Observational_studies Limits: Adolescent / Adult / Female / Humans / Male Language: En Journal: Transl Psychiatry Year: 2016 Document type: Article Affiliation country: Japan Country of publication: United States