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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3832-3843.e6
JournalCell Reports
Volume27
Issue number13
DOIs
StatePublished - Jun 25 2019

Fingerprint

Neuroglia
Schizophrenia
Bone Morphogenetic Proteins
Childhood Schizophrenia
Stem Cells
Transcription
Induced Pluripotent Stem Cells
Gene expression
Potassium
Homeostasis
Gene Expression
Defects

Keywords

  • astrocytes
  • BAMBI
  • BMP inhibitors
  • epigenetics
  • glial progenitor cells
  • iPSC
  • potassium channel
  • REST
  • schizophrenia
  • stem cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Liu, Z., Osipovitch, M., Benraiss, A., Huynh, N. P. T., Foti, R., Bates, J., ... Goldman, S. A. (2019). Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling. Cell Reports, 27(13), 3832-3843.e6. https://doi.org/10.1016/j.celrep.2019.05.088

Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling. / Liu, Zhengshan; Osipovitch, Mikhail; Benraiss, Abdellatif; Huynh, Nguyen P.T.; Foti, Rossana; Bates, Janna; Chandler-Militello, Devin; Findling, Robert L; Tesar, Paul J.; Nedergaard, Maiken; Windrem, Martha S.; Goldman, Steven A.

In: Cell Reports, Vol. 27, No. 13, 25.06.2019, p. 3832-3843.e6.

Research output: Contribution to journalArticle

Liu, Z, Osipovitch, M, Benraiss, A, Huynh, NPT, Foti, R, Bates, J, Chandler-Militello, D, Findling, RL, Tesar, PJ, Nedergaard, M, Windrem, MS & Goldman, SA 2019, 'Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling', Cell Reports, vol. 27, no. 13, pp. 3832-3843.e6. https://doi.org/10.1016/j.celrep.2019.05.088
Liu, Zhengshan ; Osipovitch, Mikhail ; Benraiss, Abdellatif ; Huynh, Nguyen P.T. ; Foti, Rossana ; Bates, Janna ; Chandler-Militello, Devin ; Findling, Robert L ; Tesar, Paul J. ; Nedergaard, Maiken ; Windrem, Martha S. ; Goldman, Steven A. / Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling. In: Cell Reports. 2019 ; Vol. 27, No. 13. pp. 3832-3843.e6.
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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.",
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AU - Benraiss, Abdellatif

AU - Huynh, Nguyen P.T.

AU - Foti, Rossana

AU - Bates, Janna

AU - Chandler-Militello, Devin

AU - Findling, Robert L

AU - Tesar, Paul J.

AU - Nedergaard, Maiken

AU - Windrem, Martha S.

AU - Goldman, Steven A.

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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. 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.

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