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 language | English (US) |
|---|---|
| Pages (from-to) | 3832-3843.e6 |
| Journal | Cell Reports |
| Volume | 27 |
| Issue number | 13 |
| DOIs | |
| State | Published - Jun 25 2019 |
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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
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 journal › Article
}
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 - 2019/6/25
Y1 - 2019/6/25
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
UR - http://www.scopus.com/inward/record.url?scp=85067290780&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067290780&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.05.088
DO - 10.1016/j.celrep.2019.05.088
M3 - Article
VL - 27
SP - 3832-3843.e6
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 13
ER -