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Copper stress induces zebrafish central neural system myelin defects via WNT/NOTCH-hoxb5b signaling and pou3f1/fam168a/fam168b DNA methylation.
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms ( IF 4.7 ) Pub Date : 2020-07-31 , DOI: 10.1016/j.bbagrm.2020.194612
Ting Zhang 1 , PengPeng Guan 2 , WenYe Liu 3 , Guang Zhao 3 , YaPing Fang 2 , Hui Fu 4 , Jian-Fang Gui 5 , GuoLiang Li 2 , Jing-Xia Liu 3
Affiliation  

Unbalanced copper (Cu) homeostasis is associated with neurological development defects and diseases. However, the molecular mechanisms remain elusive. Here, central neural system (CNS) myelin defects and the down-regulated expression of WNT/NOTCH signaling and its down-stream mediator hoxb5b were observed in Cu2+ stressed zebrafish larvae. The loss/knockdown-of-function of hoxb5b phenocopied the myelin and axon defects observed in Cu2+ stressed embryos. Meanwhile, the activation of WNT/NOTCH signaling and ectopic expression of hoxb5b could rescue Cu induced myelin defects. Additionally, fam168b, similar to pou3f1/2, exhibited significant promoter hypermethylation and reduced expression in Cu2+ stressed embryos. The hypermethylated locus in fam168b promoter acted pivotally in its transcription, and the loss/knockdown of fam168b/pou3f1 also induced myelin defects. This study also demonstrated that fam168b/pou3f1 and hoxb5b axis acted in a seesaw manner during fish embryogenesis: Cu induced the down-regulated expression of the WNT&NOTCH-hoxb5b axis through the function of copper transporter cox17, coupled with the promoter methylation of genes fam168b/pou3f1, and its subsequent down-regulated expression through the function of another transporter atp7b, making joint contributions to myelin defects in embryos.



中文翻译:

铜胁迫通过WNT / NOTCH-hoxb5b信号传导和pou3f1 / fam168a / fam168b DNA甲基化诱导斑马鱼中枢神经系统髓鞘缺陷。

铜(Cu)稳态失衡与神经系统发育缺陷和疾病有关。但是,分子机制仍然难以捉摸。在这里,在Cu 2+应激斑马鱼幼虫中观察到中枢神经系统(CNS)髓鞘缺陷和WNT / NOTCH信号及其下游介质hoxb5b的下调表达。损失/敲低-的功能的hoxb5b表型模拟在Cu中观察到的髓鞘和轴突缺陷2+强调胚胎。同时,WNT / NOTCH信号的激活和异位表达的hoxb5b可以挽救铜诱导的髓磷脂缺陷。此外,fam168b,类似于pou3f1 / 2,显示出明显的启动子高度甲基化和减少的铜2 +应激的胚胎表达。fam168b启动子中的高甲基化基因座在其转录中起关键作用,fam168b / pou3f1的丢失/敲低也诱导了髓磷脂缺陷。这项研究还表明,fam168b / pou3f1hoxb5b轴在鱼类胚胎发生过程中以跷跷板的方式起作用:Cu通过铜转运蛋白cox17的功能与基因fam168b /的启动子甲基化相结合,下调了WNT&NOTCH- hoxb5b轴的表达。pou3f1,以及随后通过另一种转运蛋白atp7b的功能下调表达,共同促进了胚胎髓磷脂的缺陷。

更新日期:2020-08-08
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