@article{ca24e84624a043c98b7b10a91e59733c,
title = "Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling",
abstract = "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. Astrocytic differentiation is impaired in childhood-onset schizophrenia (SCZ). Liu et al. report that SMAD4-dependent BMP signaling and REST are upregulated in hiPSC-derived SCZ glia and that SMAD4 and REST knockdown rescue both astroglial differentiation and K+ transport. SCZ astrocytic maturation may thus be rescued by targeting SMAD4- and REST-dependent transcription.",
keywords = "BAMBI, BMP inhibitors, REST, astrocytes, epigenetics, glial progenitor cells, iPSC, potassium channel, schizophrenia, stem cells",
author = "Zhengshan Liu and Mikhail Osipovitch and Abdellatif Benraiss and Huynh, {Nguyen P.T.} and Rossana Foti and Janna Bates and Devin Chandler-Militello and Findling, {Robert L.} and Tesar, {Paul J.} and Maiken Nedergaard and Windrem, {Martha S.} and Goldman, {Steven A.}",
note = "Funding Information: This work is supported by NIMH grants R01MH104701 and R01MH099578 , the Novo Nordisk Foundation , the Lundbeck Foundation , the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation , and the G. Harold and Leila Y. Mathers Charitable Foundation . We thank Lorenz Studer (Memorial Sloan Kettering) for the C27 hiPSC cell line and Didier Trono for the psPAX2 lentiviral vector. All genomic data have been deposited to GEO: GSE86906 . Funding Information: This work is supported by NIMH grants R01MH104701 and R01MH099578, the Novo Nordisk Foundation, the Lundbeck Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the G. Harold and Leila Y. Mathers Charitable Foundation. We thank Lorenz Studer (Memorial Sloan Kettering) for the C27 hiPSC cell line and Didier Trono for the psPAX2 lentiviral vector. All genomic data have been deposited to GEO: GSE86906. Z.L. performed all primary experiments; M.O. N.P.T.H. and R.F. performed the genomic and methylomic analyses; J.B. and Z.L. prepared the GPCs used in the study; D.C.-M. assisted Z.L. with cytometry and sorting; A.B. designed and assisted Z.L. in making the overexpression and KD viruses; M.N. and M.S.W. assisted in data analysis; R.L.F. and P.J.T. prepared the SCZ and CTR iPSCs; and S.A.G. designed the study, analyzed the data, and wrote the manuscript. The authors declare no competing interests in regards to this study. Regarding 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. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jun,
day = "25",
doi = "10.1016/j.celrep.2019.05.088",
language = "English (US)",
volume = "27",
pages = "3832--3843.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}