Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4-and REST-Dependent Signaling
Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4-and REST-Dependent Signaling
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DOI：
10.1016/j.celrep.2019.05.088
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发表时间：
2019-06-25
期刊：
影响因子：
8.8
通讯作者：
Goldman, Steven A.
中科院分区：
文献类型：
--
作者：
Liu, Zhengshan;Osipovitch, Mikhail;Goldman, Steven A.
星形胶质细胞分化在儿童期发作的精神分裂症（SCZ）患者中是发育受损的。为了确定原因，我们使用遗传获得和功能丧失研究来确定差异表达的转录调节因子对SCZ患者来源的诱导多能细胞（iPSC）产生的胶质祖细胞（GPC）分化缺陷的贡献。骨形态发生蛋白（BMP）通路的负调节因子在SCZ GPCs中上调，包括BAMBI、FST和GREM 1，其过表达使SCZ GPCs保留在祖细胞阶段。SMAD 4敲低（KD）抑制了SCZ GPCs产生这些BMP抑制剂，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 GPCs中上调，其KD同样恢复了正常的胶质细胞分化。REST KD也拯救钾转运相关基因表达和K+摄取，否则SCZ神经胶质细胞缺乏。这些数据表明，胶质细胞分化缺陷儿童期发病SCZ，其伴随的破坏K+稳态，可能会获救，通过靶向BMP/SMAD 4和REST依赖的转录。
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.