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

如果周围神经系统(PNS)受到创伤性损伤，周围神经系统(PNS)的髓鞘胶质细胞雪旺细胞(Schwann Cell)会脱髓鞘，转化为修复细胞，促进轴突再生。相比之下，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，其含有生长抑制因子的髓鞘阻止轴突再生。我们发现，抑制ERK1/2激活的磷酸酶DUSP6在培养的小鼠轴突损伤和坐骨神经挤压伤后的雪旺细胞中迅速下调，而在培养的小鼠轴突损伤和脊髓损伤后的少突胶质细胞中DUSP6迅速上调。一直以来，ERK1/2在坐骨神经损伤后在雪旺细胞中迅速激活，但在脊髓损伤后不在少突胶质细胞中激活。通过使用我们最近在微流体室内建立的损伤模型，我们发现shRNA下调少突胶质细胞中DUSP6的表达促进轴突再生。本研究的目的是阐明DUSP6在少突胶质细胞中下调是如何促进轴突再生的，以及在雪旺细胞中DUSP6下调是否是损伤后轴突再生所必需的，确定损伤后雪旺细胞和少突胶质细胞中DUSP6表达的调节机制，设计探索性的治疗方法来下调少突胶质细胞中DUSP6的表达，并测试这是否促进小鼠脊髓损伤后的轴突再生。

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.