Functions and regulation of DUSP6 in Schwann cells and oligodendrocytes after injury

当外周神经系统（PNS）受到外伤性损伤时，Schwann细胞（PNS的髓鞘胶质细胞）脱髓鞘并转化为修复细胞以促进轴突再生。相反，少突胶质细胞，即中枢神经系统（CNS）的髓鞘胶质细胞，在中枢神经系统损伤后仍处于髓鞘状态或死亡，其髓鞘中含有生长抑制因子，可阻止轴突再生。我们发现DUSP6是一种抑制ERK1/2激活的磷酸酶，在培养的雪旺细胞轴突损伤和小鼠坐骨神经挤压损伤后迅速下调，而在培养的小鼠轴突损伤和脊髓损伤后少突胶质细胞中DUSP6迅速上调。一致地，ERK1/2在坐骨神经损伤后的雪旺细胞中被迅速激活，而在脊髓损伤后的少突胶质细胞中则没有。通过我们最近在微流控室中建立的病变模型，我们发现shRNA下调少突胶质细胞中的DUSP6可促进轴突再生。本项目旨在阐明少突胶质细胞中DUSP6下调如何促进轴突再生，雪旺细胞中DUSP6下调是否为损伤后轴突再生的必要条件，明确损伤后雪旺细胞和少突胶质细胞中DUSP6表达的调控机制，设计少突胶质细胞中DUSP6下调的探索性治疗方案，并在小鼠模型中检测其是否促进脊髓损伤后轴突再生。

In case of a traumatic injury in the peripheral nervous system (PNS), Schwann cells, the myelinating glia of the PNS, demyelinate and convert into repair cells to promote axonal regrowth. In contrast, oligodendrocytes, the myelinating glia of the central nervous system (CNS), remain at their myelinating state or die after a CNS lesion and their myelin that contains growth-inhibitory factors prevents axonal regrowth. We found that DUSP6, a phosphatase that inhibits the activation of ERK1/2, is rapidly downregulated in Schwann cells after axonal lesion in culture and after a sciatic nerve crush injury in mice, whereas DUSP6 is rapidly upregulated in oligodendrocytes after axonal lesion in culture and after a spinal cord injury in mice. Consistently, ERK1/2 is rapidly activated in Schwann cells after a sciatic nerve injury, but not in oligodendrocytes after a spinal cord injury. By using lesion models that we have recently set up in microfluidic chambers, we found that downregulating DUSP6 in oligodendrocytes by shRNA promotes axonal regrowth. The aim of this project is to elucidate how DUSP6 downregulation in oligodendrocytes promotes axonal regrowth and whether DUSP6 downregulation in Schwann cells is necessary for axonal regrowth after lesion, identify the mechanisms that regulate DUSP6 expression in Schwann cells and oligodendrocytes after lesion, design exploratory treatments to downregulate DUSP6 in oligodendrocytes and test whether this promotes axonal regrowth after spinal cord injury in mouse models.