Molecular mechanisms regulating the defects in fragile X syndrome neurons derived from human pluripotent stem cells.
Molecular mechanisms regulating the defects in fragile X syndrome neurons derived from human pluripotent stem cells.
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DOI：
10.1016/j.stemcr.2014.10.015
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发表时间：
2015-01-13
影响因子：
5.9
通讯作者：
Benvenisty, Nissim
中科院分区：
文献类型：
--
作者：
Halevy, Tomer;Czech, Christian;Benvenisty, Nissim
脆性X综合征(FXS)是由脆性X智力低下蛋白(FMRP)缺失引起的。我们之前已经从患者的成纤维细胞中产生了FXS诱导的多能干细胞(IPSCs)。在这项研究中，我们旨在解开该病的分子表型。我们的数据揭示了FXS来源的神经元中神经分化和轴突引导基因的异常调节，这些基因受RE-1沉默转录因子(REST)的调节。此外，我们发现在FXS来源的神经元中，REST水平升高。由于FMRP参与了microRNA(MiRNA)途径，我们利用miRNA阵列分析发现了几个在FXS来源的神经元中调控异常的miRNAs。我们发现hsa-mir-382在FXS来源的神经元中下调，而将Mimic-mir-382导入这些神经元足以抑制REST并上调其轴突引导靶基因。我们通过miRNA途径将FMRP和REST数据链接在一起，显示了FXS发展的新局面。FXS来源的神经元显示神经和轴突引导基因的下调这些神经基因受转录抑制因子REST调控，REST在FXS来源的神经元中不受沉默，REST受hsa-mir-382调控，hsa-mir-382在FXS来源的神经元中水平较低。在本文中，Benvenisty及其同事证明脆弱的X来源神经元由于REST转录抑制因子表达升高而异常调节神经分化和轴突引导基因。他们进一步表明，高水平的休息是由于hsa-mir-382水平较低。将Mimic-mir-382引入脆弱的X来源神经元，抑制了REST，并上调了其轴突引导靶基因。
Fragile X syndrome (FXS) is caused by the absence of the fragile X mental retardation protein (FMRP). We have previously generated FXS-induced pluripotent stem cells (iPSCs) from patients’ fibroblasts. In this study, we aimed at unraveling the molecular phenotype of the disease. Our data revealed aberrant regulation of neural differentiation and axon guidance genes in FXS-derived neurons, which are regulated by the RE-1 silencing transcription factor (REST). Moreover, we found REST to be elevated in FXS-derived neurons. As FMRP is involved in the microRNA (miRNA) pathway, we employed miRNA-array analyses and uncovered several miRNAs dysregulated in FXS-derived neurons. We found hsa-mir-382 to be downregulated in FXS-derived neurons, and introduction of mimic-mir-382 into these neurons was sufficient to repress REST and upregulate its axon guidance target genes. Our data link FMRP and REST through the miRNA pathway and show a new aspect in the development of FXS. FXS-derived neurons display downregulation of neural and axon guidance genes These neural genes are regulated by the transcription repressor REST REST is not silenced in FXS-derived neurons REST is regulated by hsa-mir-382, which has lower levels in FXS-derived neurons In this article, Benvenisty and colleagues show that fragile X-derived neurons are aberrantly regulating neural differentiation and axon guidance genes due to elevated expression of the REST transcription repressor. They further suggest that the high levels of REST result from low levels of hsa-mir-382. Introduction of mimic-mir-382 into fragile X-derived neurons repressed REST and upregulated its axon guidance target genes.
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发表时间：
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影响因子：
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