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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.

Cell reports (Cambridge), 2019-06, Vol.27 (13), p.3832-3843.e6 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling
Autor: 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.
Assuntos: Adolescent ; Adult ; astrocytes ; BAMBI ; BMP inhibitors ; Cell Differentiation ; Cell Line ; Child ; epigenetics ; Female ; glial progenitor cells ; Humans ; iPSC ; Male ; Neuroglia - metabolism ; Neuroglia - pathology ; potassium channel ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; REST ; schizophrenia ; Schizophrenia - genetics ; Schizophrenia - metabolism ; Schizophrenia - pathology ; Signal Transduction ; Smad4 Protein - genetics ; Smad4 Protein - metabolism ; stem cells
É parte de: Cell reports (Cambridge), 2019-06, Vol.27 (13), p.3832-3843.e6
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Author Contributions ZL performed all primary experiments; MO, NH and RF performed the genomic and methylomic analyses; JB and ZL prepared the GPCs used in the study; DCM assisted ZL with cytometry and sorting; AB designed and assisted ZL in making the over-expression and knock-down viruses; MN and MSW assisted in data analysis; RLF and PJT prepared the SCZ and CTR iPSCs; and SAG designed the study, analyzed the data and wrote the manuscript.
Descrição: 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. [Display omitted] •Dysregulated BMP signaling restricts the differentiation of SCZ glial progenitor cells•REST is regulated by BMP/SMAD4 signaling and is overexpressed by SCZ GPCs•SMAD4 knockdown rescues normal astrocytic differentiation by SCZ GPCs•REST knockdown rescues K+ transporter gene expression and K+ uptake by SCZ glia 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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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.

United States: Elsevier Inc

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