title: DISC1 (disrupted-in-schizophrenia-1) regulates differentiation of oligodendrocytes.
abstract: Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.
authors: Department of Molecular Neuropsychiatry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors: Tsuyoshi
authors: T
authors: Hattori
authors: Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Sayama, Osaka, Japan.
authors: Shoko
authors: S
authors: Shimizu
authors: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors: Yoshihisa
authors: Y
authors: Koyama
authors: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co, Ltd, Suita, Osaka, Japan.
authors: Hisayo
authors: H
authors: Emoto
authors: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co, Ltd, Suita, Osaka, Japan.
authors: Yuji
authors: Y
authors: Matsumoto
authors: Department of Neurobiology and Anatomy, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
authors: Natsuko
authors: N
authors: Kumamoto
authors: Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan.
authors: Kohei
authors: K
authors: Yamada
authors: Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan.
authors: Hironori
authors: H
authors: Takamura
authors: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan.
authors: Shinsuke
authors: S
authors: Matsuzaki
authors: Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan.
authors: Taiichi
authors: T
authors: Katayama
authors: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan ; Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Sayama, Osaka, Japan.
authors: Masaya
authors: M
authors: Tohyama
authors: Department of Molecular Neuropsychiatry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors: Akira
authors: A
authors: Ito
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000166:cytology / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
chemical_list: C498794:Disc1 protein, mouse; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C000715627:Nkx2-2 protein, mouse; C000715628:Nkx2-2 protein, rat; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish