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.
Pubmed ID: 31242417 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This monoclonal targets Mouse Human SSEA-4 (carbohydrate from human embryonal carcinoma)
View all literature mentionsThis polyclonal targets Human SOX1
View all literature mentionsThis isotype control targets Isotype Control
View all literature mentionsThis monoclonal targets CD133/1 (AC133)
View all literature mentionsThis monoclonal targets CD140a
View all literature mentionsThis monoclonal targets Rat Mouse IgG2a+b MicroBeads
View all literature mentionsThis monoclonal targets CD140a
View all literature mentionsThis monoclonal targets CD44
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal secondary targets Mouse IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis monoclonal targets S100 beta antibody [SH-B1]
View all literature mentionsThis polyclonal targets Pax-6
View all literature mentionsThis monoclonal targets GFAP
View all literature mentionsThis monoclonal targets PDGF Receptor (D13C6) XP Rabbit mAb
View all literature mentionsThis monoclonal targets HSP90B1
View all literature mentionsThis unknown targets Nanog
View all literature mentionsThis polyclonal targets Human SOX1
View all literature mentions