Ketamine Modulates Zic5 Expression via the Notch Signaling Pathway in Neural Crest Induction.
Ketamine Modulates Zic5 Expression via the Notch Signaling Pathway in Neural Crest Induction.
复制标题
氯胺酮通过神经嵴诱导中的 Notch 信号通路调节 Zic5 表达
DOI：
10.3389/fnmol.2018.00009
复制
发表时间：
2018
影响因子：
4.8
通讯作者：
Song W
中科院分区：
文献类型：
--
作者：
Shi Y;Li J;Chen C;Xia Y;Li Y;Zhang P;Xu Y;Li T;Zhou W;Song W
氯胺酮是一种强效的分离性麻醉剂，也是最常用的违禁药物。许多吸毒者是育龄妇女。虽然氯胺酮作为临床麻醉剂已被广泛研究，但其对胚胎发育的影响知之甚少。在这里，我们应用非洲爪蟾模型来研究氯胺酮对发育的影响。我们发现，从原肠胚形成前（第7阶段）到早期神经板（第13.5阶段）暴露于氯胺酮导致神经嵴（NC）衍生物破坏。氯胺酮暴露不影响中胚层发育，如由Chordin、Xbra、Wnt 8和Fgf 8的正常表达所指示的。然而，氯胺酮处理显著抑制Zic 5和Slug在早期神经板阶段的表达。Zic 5的过表达挽救了氯胺酮诱导的Slug抑制，表明NC诱导的阻断是由Zic 5介导的。此外，我们发现Notch信号被氯胺酮改变。氯胺酮抑制Notch靶基因的表达，包括Hes5.2a，Hes5.2b和ESR 1，氯胺酮处理的胚胎表现出Notch缺陷的体节表型。Zic 5上游15 bp的核心结合元件由Notch信号传导诱导并引起转录激活。这些结果表明Zic 5在爪蟾NC诱导中作为Notch信号传导的下游靶基因起作用。我们的研究提供了一种新的致畸机制，氯胺酮通过靶向Notch-Zic 5信号通路破坏NC诱导。
Ketamine is a potent dissociative anesthetic and the most commonly used illicit drug. Many addicts are women at childbearing age. Although ketamine has been extensively studied as a clinical anesthetic, its effects on embryonic development are poorly understood. Here, we applied the Xenopus model to study the effects of ketamine on development. We found that exposure to ketamine from pre-gastrulation (stage 7) to early neural plate (stage 13.5) resulted in disruption of neural crest (NC) derivatives. Ketamine exposure did not affect mesoderm development as indicated by the normal expression of Chordin, Xbra, Wnt8, and Fgf8. However, ketamine treatment significantly inhibited Zic5 and Slug expression at early neural plate stage. Overexpression of Zic5 rescued ketamine-induced Slug inhibition, suggesting the blockage of NC induction was mediated by Zic5. Furthermore, we found Notch signaling was altered by ketamine. Ketamine inhibited the expression of Notch targeted genes including Hes5.2a, Hes5.2b, and ESR1 and ketamine-treated embryos exhibited Notch-deficient somite phenotypes. A 15 bp core binding element upstream of Zic5 was induced by Notch signaling and caused transcriptional activation. These results demonstrated that Zic5 works as a downstream target gene of Notch signaling in Xenopus NC induction. Our study provides a novel teratogenic mechanism whereby ketamine disrupts NC induction via targeting a Notch-Zic5 signaling pathway.
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DOI：
10.4088/jcp.09m05327blu
发表时间：
2010-12
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
DiazGranados N;Ibrahim LA;Brutsche NE;Ameli R;Henter ID;Luckenbaugh DA;Machado-Vieira R;Zarate CA Jr
通讯作者：
Zarate CA Jr
影响因子：
3.8
作者：
Felix, Luis M.;Serafim, Cindy;Coimbra, Ana M.
通讯作者：
Coimbra, Ana M.
影响因子：
5.3
作者：
Bozkulak, Esra Cagavi;Weinmaster, Gerry
通讯作者：
Weinmaster, Gerry
影响因子：
5.7
作者：
Bai X;Yan Y;Canfield S;Muravyeva MY;Kikuchi C;Zaja I;Corbett JA;Bosnjak ZJ
通讯作者：
Bosnjak ZJ
DOI：
10.1073/pnas.1010740107
发表时间：
2011-01-04
影响因子：
11.1
作者：
de Croze, Noemie;Maczkowiak, Frederique;Monsoro-Burq, Anne H.
通讯作者：
Monsoro-Burq, Anne H.