Guardian of myelin and neural Integrity: foxo1a through slc7a11 mitigating oxidative damage in myelin

TL;DR

This study shows that foxo1a helps protect myelin in zebrafish by reducing oxidative damage, offering insights into neural evolution in jawed vertebrates.

Contribution

The study reveals foxo1a's role in myelin protection through slc7a11, suggesting an evolutionarily conserved neural defense strategy.

Findings

Knocking out foxo1a in zebrafish causes abnormal myelin development and reduced oligodendrocytes and astrocytes.

Foxo1a regulates oxidative stress and iron homeostasis via slc7a11 in the central nervous system.

Exogenous foxo1a supplementation protects against copper sulfate-induced myelin damage in zebrafish.

Abstract

The emergence of myelin marks an evolutionary leap from jawless to jawed vertebrates. Although myelin's role in promoting rapid neural signal transmission and brain complexity is known, its neuroprotective mechanisms in complex signal transmission remain unclear. This study identifies the critical FoxO gene family member, foxo1a, as essential to the evolution of jawed vertebrates by comparing divergence times and gene family heterogeneity between jawless and jawed vertebrates. We found that foxo1a is located in zebrafish oligodendrocytes and myelin, playing a key antioxidant protective role. Specifically, we found that knocking out the foxo1a gene leads to abnormal myelin development in the central nervous system of zebrafish, a reduction in oligodendrocytes, astrocytes, and myelin markers, and induces freezing behavior. Further research revealed that this is related to oxidative stress responses and ferroptosis in the central nervous system of zebrafish following the deficiency of the foxo1a gene. Mechanistically, we discovered that foxo1a is involved in regulating oxidative stress responses and iron homeostasis in the central nervous system by directly regulating the promoter activity of the slc7a11 gene. In terms of application, we found that exogenous supplementation of foxo1a can exert antioxidant protective effects in a copper sulfate-induced myelin damage model. More importantly, we found a parallelism of the foxo1a-slc7a11 axis in both zebrafish and human cells, suggesting that the foxo1a-slc7a11 axis might be an evolutionarily conserved neural defense strategy in jawed vertebrates. In conclusion, our study elucidates the critical role of foxo1a in maintaining antioxidant homeostasis in the central nervous system and provides new insights into the adaptive evolution of the central nervous system in jawed vertebrates.

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