PMID- 31242417 OWN - NLM STAT- MEDLINE DCOM- 20200730 LR - 20210116 IS - 2211-1247 (Electronic) VI - 27 IP - 13 DP - 2019 Jun 25 TI - Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling. PG - 3832-3843.e6 LID - S2211-1247(19)30727-2 [pii] LID - 10.1016/j.celrep.2019.05.088 [doi] AB - Astrocytic differentiation is developmentally impaired in patients with childhood-onset schizophrenia (SCZ). To determine why, we used genetic gain- and loss-of-function studies to establish the contributions of differentially expressed transcriptional regulators to the defective differentiation of glial progenitor cells (GPCs) produced from SCZ patient-derived induced pluripotent cells (iPSCs). Negative regulators of the bone morphogenetic protein (BMP) pathway were upregulated in SCZ GPCs, including BAMBI, FST, and GREM1, whose overexpression retained SCZ GPCs at the progenitor stage. SMAD4 knockdown (KD) suppressed the production of these BMP inhibitors by SCZ GPCs and rescued normal astrocytic differentiation. In addition, the BMP-regulated transcriptional repressor REST was upregulated in SCZ GPCs, and its KD similarly restored normal glial differentiation. REST KD also rescued potassium-transport-associated gene expression and K(+) uptake, which were otherwise deficient in SCZ glia. These data suggest that the glial differentiation defect in childhood-onset SCZ, and its attendant disruption in K(+) homeostasis, may be rescued by targeting BMP/SMAD4- and REST-dependent transcription. CI - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Liu, Zhengshan AU - Liu Z AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. FAU - Osipovitch, Mikhail AU - Osipovitch M AD - Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark. FAU - Benraiss, Abdellatif AU - Benraiss A AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. FAU - Huynh, Nguyen P T AU - Huynh NPT AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. FAU - Foti, Rossana AU - Foti R AD - Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark. FAU - Bates, Janna AU - Bates J AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. FAU - Chandler-Militello, Devin AU - Chandler-Militello D AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. FAU - Findling, Robert L AU - Findling RL AD - Department of Psychiatry, Johns Hopkins Medical School, Baltimore, MD, USA. FAU - Tesar, Paul J AU - Tesar PJ AD - Department of Genetics, Case Western University Medical School, Cleveland, OH 44106, USA. FAU - Nedergaard, Maiken AU - Nedergaard M AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark. FAU - Windrem, Martha S AU - Windrem MS AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. FAU - Goldman, Steven A AU - Goldman SA AD - Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark; Neuroscience Center, Rigshospitalet, Copenhagen, Denmark. Electronic address: steven_goldman@urmc.rochester.edu. LA - eng GR - R01 AG048769/AG/NIA NIH HHS/United States GR - R01 MH104701/MH/NIMH NIH HHS/United States GR - R01 MH099578/MH/NIMH NIH HHS/United States GR - R01 NS110776/NS/NINDS NIH HHS/United States GR - RF1 NS110049/NS/NINDS NIH HHS/United States GR - R01 NS100366/NS/NINDS NIH HHS/United States GR - RF1 AG057575/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (RE1-silencing transcription factor) RN - 0 (Repressor Proteins) RN - 0 (SMAD4 protein, human) RN - 0 (Smad4 Protein) SB - IM MH - Adolescent MH - Adult MH - *Cell Differentiation MH - Cell Line MH - Child MH - Female MH - Humans MH - Male MH - Neuroglia/*metabolism/pathology MH - Repressor Proteins/genetics/*metabolism MH - Schizophrenia/genetics/*metabolism/pathology MH - *Signal Transduction MH - Smad4 Protein/genetics/*metabolism PMC - PMC6700735 MID - NIHMS1042525 OTO - NOTNLM OT - BAMBI OT - BMP inhibitors OT - REST OT - astrocytes OT - epigenetics OT - glial progenitor cells OT - iPSC OT - potassium channel OT - schizophrenia OT - stem cells COIS- Declaration of Interests: The authors declare no competing interests in regards to this study. In regards to other, non-overlapping studies, Dr. Goldman is a co-founder and officer of Oscine Corp., a cell therapy company, and Drs. Goldman and Windrem are co-inventors on US and EU patents describing human glial chimeric mice and their use in modeling glial disorders. None of the other authors have any known conflicts of interest in regards to this work. EDAT- 2019/06/27 06:00 MHDA- 2020/07/31 06:00 PMCR- 2019/08/20 CRDT- 2019/06/27 06:00 PHST- 2018/12/22 00:00 [received] PHST- 2019/04/04 00:00 [revised] PHST- 2019/05/22 00:00 [accepted] PHST- 2019/06/27 06:00 [entrez] PHST- 2019/06/27 06:00 [pubmed] PHST- 2020/07/31 06:00 [medline] PHST- 2019/08/20 00:00 [pmc-release] AID - S2211-1247(19)30727-2 [pii] AID - 10.1016/j.celrep.2019.05.088 [doi] PST - ppublish SO - Cell Rep. 2019 Jun 25;27(13):3832-3843.e6. doi: 10.1016/j.celrep.2019.05.088.