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bioRxiv · 10.1101/2019.12.16.877860

Copper Induces Zebrafish Central Neural System Myelin Defects: the Regulatory Mechanisms in Wnt/Notch-hoxb5b Signaling and Underlying DNA Methylation

Zhang, T.·Guan, P.·Zhao, G.·Fang, Y.·Fu, H.·Gui, J.·Li, G.·Liu, J.-X.
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Abstract

Unbalanced copper (Cu2+) homeostasis is associated with neurological development defects and diseases. However, the molecular mechanisms remain elusive. Here, central neural system (CNS) myelin defects and down-regulated expression of Wnt/Notch signaling and their down-stream mediator hoxb5b were observed in Cu2+ stressed zebrafish larvae. Loss/knockdown-of-function of hoxb5b phenocopied the myelin and axon defects observed in Cu2+ stressed embryos. Meanwhile, activation of Wnt/Notch signaling and ectopic expression of hoxb5b could rescue copper-induced myelin defects, suggesting Wnt&Notch-hoxb5b axis mediated Cu2+ induced myelin and axon defects. Additionally, whole genome DNA methylation sequencing unveiled that a novel gene 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 loss/knockdown of fam168b/pou3f1 also induced myelin defects. Moreover, this study unveiled that fam168b/pou3f1 and hoxb5b axis acted in a seesaw manner during fish embryogenesis, and demonstrated that copper induced the down-regulated expression of the Wnt&Notch-hoxb5b axis dependent of the function of copper transporter cox17, coupled with the promoter methylation of genes fam168b/pou3f1 and their subsequent down-regulated expression dependent of the function of another transporter atp7b, making joint contributions to myelin defects in embryos. Those data will shed some light on the linkage of unbalanced copper homeostasis with specific gene promoter methylation and signaling transduction as well as the resultant neurological development defects and diseases. Author summaryIn this study, we first unveiled that copper induced central neural system (CNS) myelin defects via down-regulating Wnt/Notch-hoxb5b signaling, and parallel with hypermethylating promoters of genes fam168b/pou3f2 and their subsequent down-regulated expression. Additionally, we unveiled that fam168b/pou3f1 and hoxb5b axis acted in a seesaw manner during fish embryogenesis. Genetically, we unveiled that copper was trafficked to mitochondrion via cox17 then led to the down-regulation of Wnt&Notch-hoxb5b axis, and was trafficked to trans-Golgi network via atp7b to induce the hypermethylation and the down-regulated expression of pou3f1/fam168b genes, making joint contributions to myelin defects in embryos.

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Zhang, T., Guan, P., Zhao, G., Fang, Y., Fu, H., Gui, J., Li, G., Liu, J.-X.. 2019-12-16. Copper Induces Zebrafish Central Neural System Myelin Defects: the Regulatory Mechanisms in Wnt/Notch-hoxb5b Signaling and Underlying DNA Methylation. https://doi.org/10.1101/2019.12.16.877860

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