Olig2-Targeted G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Survival in Response to Lysolecithin-Induced Demyelination
Olig2-Targeted G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Survival in Response to Lysolecithin-Induced Demyelination
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Olig2 靶向 G 蛋白偶联受体 Gpr17 调节少突胶质细胞存活以响应溶血卵磷脂诱导的脱髓鞘
DOI：
10.1523/jneurosci.0898-16.2016
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发表时间：
2016-10-12
影响因子：
5.3
通讯作者：
Chen, Ying
中科院分区：
文献类型：
--
作者：
Ou, Zhimin;Sun, Yuxia;Chen, Ying
脱髓鞘疾病，如多发性硬化症，已知是由髓鞘急性或慢性损伤和髓鞘再生不足引起的；然而，潜在的分子机制尚不清楚。在这里，我们通过染色质免疫沉淀测序对少突胶质细胞进行了基因组占用分析，以响应溶卵磷脂诱导的损伤，发现Olig2及其下游靶点Gpr17是调节少突胶质细胞存活的关键因素。少突胶质细胞损伤后，Olig2显著上调，并转录靶向Gpr17位点。Gpr17激活通过降低细胞内cAMP水平和诱导促凋亡基因Xaf1的表达来抑制少突胶质细胞的存活。蛋白激酶A信号通路和转录因子c-Fos介导Gpr17在少突胶质细胞中的调节作用。我们发现抑制Gpr17可提高Epac1的表达，促进少突胶质细胞的分化。Gpr17的缺失，无论是全局缺失还是少突胶质细胞特异性缺失，都会导致小鼠髓鞘损伤后髓鞘再生的早期发生。同样，普氨司特对Gpr17的药理学抑制可促进髓鞘再生。我们的研究结果表明，Olig2转录靶点Gpr17在少突胶质细胞损伤后被激活，靶向抑制Gpr17可促进少突胶质细胞再髓鞘形成。少突胶质细胞对溶卵磷脂介导的脱髓鞘损伤的基因组占据分析表明，Olig2及其下游靶点Gpr17是少突胶质细胞存活的关键调控回路的一部分。Gpr17通过激活Xaf1抑制少突胶质细胞存活，并通过降低Epac1表达抑制细胞分化。小鼠中Gpr17的缺失导致髓鞘形成早发性和脱髓鞘后的再髓鞘形成提早发生。Gpr17的药理抑制促进了脱髓鞘再生，突出了Gpr17靶向治疗脱髓鞘疾病的潜力。
Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of the pro-apoptotic gene Xaf1. The protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevated Epac1 expression and promoted oligodendrocyte differentiation. The loss of Gpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate that Gpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination. SIGNIFICANCE STATEMENT Genome occupancy analysis of oligodendrocytes in response to lysolecithin-mediated demyelination injury revealed that Olig2 and its downstream target Gpr17 are part of regulatory circuitry critical for oligodendrocyte survival. Gpr17 inhibits oligodendrocyte survival through activation of Xaf1 and cell differentiation by reducing Epac1 expression. The loss of Gpr17 in mice led to precocious myelination and an earlier onset of remyelination after demyelination. Pharmacological inhibition of Gpr17 promoted remyelination, highlighting the potential for Gpr17-targeted therapeutic approaches in demyelination diseases.