After a spinal cord injury, axons fail to regrow, which results in permanent loss of function¹. This is in contrast with peripheral axons that can regrow efficiently after injury². These differences are partly due to the different plasticity of myelinating cells, Schwann cells and oligodendrocytes, in these two systems³. The molecular mechanisms underlying this different plasticity remain however poorly understood. Here, we show that the phosphatase Dusp6⁴ 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.

中文翻译：

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损伤后修复少突胶质细胞脱髓鞘和崩解受损轴突

脊髓损伤后，轴突无法再生，导致功能永久丧失¹。这与外周轴突形成对比，外周轴突可以在受伤后有效地再生²。这些差异部分是由于这两个系统中髓鞘形成细胞、雪旺细胞和少突胶质细胞的可塑性不同³。然而，这种不同可塑性背后的分子机制仍然知之甚少。在这里，我们表明磷酸酶 Dusp6 ⁴是脊髓损伤后少突胶质细胞可塑性的主要抑制剂。Dusp6 在施万细胞中迅速下调，在轴突损伤后在少突胶质细胞中上调。同时，MAP 激酶 ERK1/2 被激活，转录因子 c-Jun 在雪旺细胞中上调^5,6, 但不在少突胶质细胞中。Dusp6 的消融或失活会诱导少突胶质细胞中的快速 ERK1/2 磷酸化、c-Jun 上调和丝状伪足形成，从而导致机械诱导的受损轴突远端的快速崩解、髓鞘清除和轴突再生。总之，我们的研究结果提供了对受伤后雪旺细胞和少突胶质细胞不同可塑性的潜在机制的理解，以及将表现出轴突再生抑制信号的成熟少突胶质细胞转化为修复少突胶质细胞的方法，让人联想到修复雪旺细胞。我们表明，修复少突胶质细胞成功地增加了脊髓环境与损伤后轴突再生的相容性，表明修复少突胶质细胞可能用作未来治疗脊髓损伤的治疗方法。