Copper stress induces zebrafish central neural system myelin defects via WNT/NOTCH-hoxb5b signaling and pou3f1/fam168a/fam168b DNA methylation

Ting Zhang,Pengpeng Guan,Wenye Liu,Guang Zhao,Yaping Fang,Hui Fu,Jian-Fang Gui,Guoliang Li,Jing-Xia Liu

doi:10.1016/j.bbagrm.2020.194612

Abstract

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.

Highlights

Many neurological diseases with behavioral changes and neurological disorders are associated with the unbalanced copper homeostasis in human, such as Alzheimer’s disease (AD), Wilson’s disease (WD)
Myelin disorder in human has been reported to associate with a series of neurodegenerative diseases such as multiple sclerosis (MS), Menkes diseases (MD), Parkinson’s diseases (PD) and Huntington’s diseases (HD) [14, 15]
Transmission electron microscopy (TEM) detection revealed compacted myelin sheaths in the spinal cord in the control larvae at 5 dpf (Fig 1A1-A2), but significantly thinner and uncompacted myelin in the spinal cord in Cu2+ stressed larvae (Figs 1A3-A5)

Summary

Introduction

Many neurological diseases with behavioral changes and neurological disorders are associated with the unbalanced copper homeostasis in human, such as Alzheimer’s disease (AD), Wilson’s disease (WD)and Wallerian degeneration (WD)(1, 2). Excess copper has been reported to damage nervous system and lead to the behavioral abnormalities in fish [3, 4]. Axonal damage has been shown to cause neurological disorders, such as stroke, traumatic brain/spinal cord injuries, multiple sclerosis (MS) and Wallerian degeneration (WD) [5, 6]. Myelin sheaths are essential for the rapid and efficient propagation of action potentials as well as for the support for the integrity of axons in the vertebrate nervous system. In the central nervous system (CNS), oligodendrocytes spirally wrap axons in multilamellar plasma membrane and eventually compact to form the myelin sheaths [7, 8]. Myelin disorder in human has been reported to associate with a series of neurodegenerative diseases such as MS, Menkes diseases (MD), Parkinson’s diseases (PD) and Huntington’s diseases (HD) [14, 15]

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Conclusion