Repair oligodendrocytes demyelinating and disintegrating damaged axons after injury

After a spinal cord injury, axons fail to regrow, which results in permanent loss of function 1 . This is in contrast with peripheral axons that can regrow efficiently after injury 2 . These differences are partly due to the different plasticity of myelinating cells, Schwann cells and oligodendrocytes, in these two systems 3 . The molecular mechanisms underlying this different plasticity remain however poorly understood. Here, we show that the phosphatase Dusp6 4 is a master 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 factor c-Jun is upregulated in Schwann cells 5,6 , but not in oligodendrocytes. Ablation or inactivation of Dusp6 induces rapid ERK1/2 phosphorylation, c-Jun upregulation and filopodia formation in oligodendrocytes, leading to mechanically-induced, fast disintegration of distal ends of injured axons, myelin clearance and axonal regrowth. Together, our findings provide understanding of the mechanisms underlying the different plasticity of Schwann cells and oligodendrocytes after injury and a 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, suggesting a potential use of repair oligodendrocytes as future therapeutic approach to treat spinal cord injuries.