Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark.
Cell Rep. 2019 Jun 25;27(13):3832-3843.e6. doi: 10.1016/j.celrep.2019.05.088.
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.
星形胶质细胞分化在儿童发病型精神分裂症（SCZ）患者中发育受损。为了确定原因，我们使用遗传增益和缺失功能研究来确定差异表达的转录调节因子对源自 SCZ 患者诱导多能干细胞（iPSC）的神经胶质前体细胞（GPC）的缺陷分化的贡献。骨形态发生蛋白（BMP）途径的负调节剂在 SCZ GPC 中上调，包括 BAMBI、FST 和 GREM1，其过表达使 SCZ GPC 保持在祖细胞阶段。SMAD4 敲低（KD）抑制了 SCZ GPC 中这些 BMP 抑制剂的产生，并挽救了正常的星形胶质细胞分化。此外，BMP 调节的转录抑制因子 REST 在 SCZ GPC 中上调，其 KD 同样恢复了正常的神经胶质分化。REST KD 还挽救了钾转运相关基因的表达和 K 摄取，否则 SCZ 神经胶质中这些都会缺失。这些数据表明，儿童发病型 SCZ 的神经胶质分化缺陷及其伴随的 K 稳态破坏，可以通过靶向 BMP/SMAD4 和 REST 依赖性转录来挽救。
