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bioRxiv · 10.1101/2023.04.19.537450

Wnt5a-Ror2 signaling activates p62-Nrf2 axis in reactive astrocytes after brain injury

Endo, M.·Tanaka, Y.·Fukuoka, M.·Suzuki, H.·Minami, Y.
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Abstract

In the brains under pathological conditions, astrocytes become reactive astrocytes that exhibit various context-dependent functions through the regulation of specific signaling pathways and transcriptional mechanisms in response to environmental changes. Reactive astrocytes induced in injured brains begin proliferating and play a role in promoting protection and repair of damaged tissues, but the relationship between the proliferative characteristics and tissue-protective and repair functions of reactive astrocytes remains unclear. Here, we show that growth factor signaling elicited by bFGF and HB-EGF, whose expression is up-regulated in the injured brains, acts synergistically with inflammatory cytokine signaling in astrocytes, thereby markedly up-regulating gene expression of the Ror-family protein Ror2, a receptor for Wnt5a. Activation of Wnt5a-Ror2 signaling in astrocytes results in intracellular accumulation of phosphorylated p62, thereby activating antioxidative transcription factor Nrf2. Finally, we provide evidence demonstrating that forced activation of Wnt5a-Ror2-p62-Nrf2 signaling axis in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.

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Endo, M., Tanaka, Y., Fukuoka, M., Suzuki, H., Minami, Y.. 2023-04-20. Wnt5a-Ror2 signaling activates p62-Nrf2 axis in reactive astrocytes after brain injury. https://doi.org/10.1101/2023.04.19.537450

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