Dusp6 ablation in oligodendrocytes induces a repair-like phenotype and promotes disintegration of damaged axons and axonal regrowth after injury
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Abstract
Following a spinal cord injury, central nervous system axons fail to regrow, which often results
1
in permanent loss of function . In contrast, peripheral axons are able to regrow efficiently after
2
injury . These differences are partly due to the different plasticity of myelinating cells,
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Schwann cells and oligodendrocytes, in these two systems . The molecular mechanisms
responsible for this different plasticity remain however poorly understood. Here, we show that the phosphatase Dusp64 acts as a key inhibitor of oligodendrocyte plasticity after spinal cord injury. Dusp6 is rapidly downregulated in Schwann cells and upregulated in oligodendrocytes after axon injury. Simultaneously, the MAP kinases ERK1/2 are activated and the transcription
5,6
factor c-Jun is upregulated in Schwann cells , but not in oligodendrocytes. Ablation or
inactivation of Dusp6 in oligodendrocytes induces rapid ERK1/2 phosphorylation, c-Jun upregulation and filopodia formation, leading to mechanically-induced, fast disintegration of distal ends of injured axons, myelin protein downregulation and axonal regrowth. Taken together, our findingsprovide a better understanding of themechanisms underlying the different plasticity of Schwann cells and oligodendrocytes after injury and a promising method to convert mature oligodendrocytes, exhibiting inhibitory cues for axonal regrowth, into repair oligodendrocytes reminiscent of repair Schwann cells. We show that repair oligodendrocytes successfully increase the compatibility of the spinal cord environment with axonal regrowth after injury and we provide a therapeutic approach to induce this process