Dusp4 Contributes to Anesthesia Neurotoxicity via Mediated Neural Differentiation in Primates
Dusp4 Contributes to Anesthesia Neurotoxicity via Mediated Neural Differentiation in Primates
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Dusp4 通过介导灵长类动物的神经分化导致麻醉神经毒性
DOI：
10.3389/fcell.2020.00786
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发表时间：
2020-08-19
影响因子：
5.5
通讯作者：
Jiang, Hong
中科院分区：
文献类型：
--
作者：
Yan, Jia;Li, Jingjie;Jiang, Hong
背景：儿童多次暴露在麻醉环境中，在发育过程中可能会出现认知功能障碍。其潜在机制已被揭示为麻醉导致幼年啮齿动物和猴子的认知缺陷。然而，七氟醚诱导神经发育毒性的分子机制尚不清楚。方法将猕猴前额叶皮质RNA测序与人类神经分化相结合，探讨七氟醚对灵长类动物的神经毒性作用机制。结果七氟醚治疗后，非人灵长类动物的双特异性蛋白磷酸酶4(Dusp4)水平明显下调。我们进一步揭示了Dusp4在人类胚胎干细胞神经分化过程中的动态表达，发现Dusp4基因的敲除可以显著抑制人类神经分化。结论Dusp4在七氟醚抑制非人类灵长类动物神经分化和调节人类神经分化中起重要作用。提示Dusp4是预防七氟醚神经毒性的潜在治疗靶点。
Background Children who are exposed to anesthesia multiple times may undergo cognitive impairment during development. The underlying mechanism has been revealed as anesthesia-induced cognitive deficiency in young rodents and monkeys. However, the molecular mechanism of sevoflurane-induced neural development toxicity is unclear. Methods By combining RNA sequencing analysis of macaques’ prefrontal cortex and human neural differentiation, this study investigates the mechanism of sevoflurane-induced neurotoxicity in primates. Results The level of dual specificity protein phosphatase 4 (Dusp4) was significantly downregulated in non-human primates after sevoflurane treatment. We further uncovered the dynamical expression of Dusp4 during the human neural differentiation of human embryonic stem cells and found that knockdown of Dusp4 could significantly inhibit human neural differentiation. Conclusion This study indicated that Dusp4 is critically involved in the sevoflurane-induced inhibition of neural differentiation in non-human primate and the regulation of human neural differentiation. It also suggested that Dusp4 is a potential therapeutic target for preventing the sevoflurane-induced neurotoxicity in primates.