Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling
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 differenti...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719307272 |
| _version_ | 1818612778905108480 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhengshan Liu |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-16T15:51:38Z |
| format | Article |
| id | doaj.art-16ab12112b63407da85af17b18749977 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-16T15:51:38Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-16ab12112b63407da85af17b187499772022-12-21T22:25:41ZengElsevierCell Reports2211-12472019-06-01271338323843.e6Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent SignalingZhengshan Liu0Mikhail Osipovitch1Abdellatif Benraiss2Nguyen P.T. Huynh3Rossana Foti4Janna Bates5Devin Chandler-Militello6Robert L. Findling7Paul J. Tesar8Maiken Nedergaard9Martha S. Windrem10Steven A. Goldman11Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, DenmarkCenter for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, DenmarkCenter for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Psychiatry, Johns Hopkins Medical School, Baltimore, MD, USADepartment of Genetics, Case Western University Medical School, Cleveland, OH 44106, USACenter 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, DenmarkCenter for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USACenter 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 authorSummary: 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, BAMBIhttp://www.sciencedirect.com/science/article/pii/S2211124719307272 |
| spellingShingle | 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 Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling Cell Reports |
| title | Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling |
| title_full | Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling |
| title_fullStr | Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling |
| title_full_unstemmed | Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling |
| title_short | Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling |
| title_sort | dysregulated glial differentiation in schizophrenia may be relieved by suppression of smad4 and rest dependent signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719307272 |
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