Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling
Zhengshan Liu,
Mikhail Osipovitch,
Abdellatif Benraiss,
Nguyen P.T. Huynh,
Rossana Foti,
Janna Bates,
Devin Chandler-Militello,
Robert L. Findling,
Paul J. Tesar,
Maiken Nedergaard,
Martha S. Windrem,
Steven A. Goldman
Affiliations
Zhengshan Liu
Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Mikhail Osipovitch
Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark
Abdellatif Benraiss
Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Nguyen P.T. Huynh
Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Rossana Foti
Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark
Janna Bates
Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Devin Chandler-Militello
Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Robert L. Findling
Department of Psychiatry, Johns Hopkins Medical School, Baltimore, MD, USA
Paul J. Tesar
Department of Genetics, Case Western University Medical School, Cleveland, OH 44106, USA
Maiken Nedergaard
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
Martha S. Windrem
Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Steven A. Goldman
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; Corresponding author
Summary: 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: schizophrenia, stem cells, iPSC, astrocytes, glial progenitor cells, epigenetics, REST, potassium channel, BMP inhibitors, BAMBI
