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

doi:10.1016/j.celrep.2019.05.088

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^*

^*Corresponding author af dette arbejde

13 Citationer (Scopus)

17 Downloads (Pure)

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.

Originalsprog	Engelsk
Tidsskrift	Cell Reports
Vol/bind	27
Udgave nummer	13
Sider (fra-til)	3832-3843, e1-e6
ISSN	2211-1247
DOI	https://doi.org/10.1016/j.celrep.2019.05.088
Status	Udgivet - 2019

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10.1016/j.celrep.2019.05.088Licens: CC BY-NC-ND

Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent SignalingForlagets udgivne version, 12,5 MBLicens: CC BY-NC-ND

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Liu, Z., Osipovitch, M., Benraiss, A., Huynh, N. P. T., Foti, R., Bates, J., Chandler-Militello, D., Findling, R. L., Tesar, P. J., Nedergaard, M., Windrem, M. S., & 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, e1-e6. https://doi.org/10.1016/j.celrep.2019.05.088

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, bind 27, nr. 13, s. 3832-3843, e1-e6. https://doi.org/10.1016/j.celrep.2019.05.088

@article{a74c27ad4c5d487099883be8901444ba,

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 = "astrocytes, BAMBI, BMP inhibitors, epigenetics, glial progenitor cells, iPSC, potassium channel, REST, 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.}",

year = "2019",

doi = "10.1016/j.celrep.2019.05.088",

language = "English",

volume = "27",

pages = "3832--3843, e1--e6",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "13",

}

TY - JOUR

T1 - Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling

AU - Liu, Zhengshan

AU - Osipovitch, Mikhail

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.

PY - 2019

Y1 - 2019

N2 - 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.

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.

KW - astrocytes

KW - BAMBI

KW - BMP inhibitors

KW - epigenetics

KW - glial progenitor cells

KW - iPSC

KW - potassium channel

KW - REST

KW - schizophrenia

KW - stem cells

U2 - 10.1016/j.celrep.2019.05.088

DO - 10.1016/j.celrep.2019.05.088

M3 - Journal article

C2 - 31242417

AN - SCOPUS:85067290780

SN - 2211-1247

VL - 27

SP - 3832-3843, e1-e6

JO - Cell Reports

JF - Cell Reports

IS - 13

ER -

Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling

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