A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord

抽象的

脊髓损伤后轴突修复能力有限的能力是长期功能障碍的基础。双亮氨酸Zipper激酶[DLK;MAP激酶激酶激酶12;MAP3K12]是一种进化保守的MAP3K秀丽隐杆线虫致哺乳动物。但是，无论是DLK还是其近距离同源亮氨酸拉链激酶（LZK; MAP3K13）调节哺乳动物脊髓中的轴突修复仍然未知。在这里，我们评估了内源性DLK和LZK在两性男性小鼠中皮质脊髓束（CST）轴突的再生和补偿性发芽中的作用，并在PTEN DELETION提供的再生背景下具有遗传分析。我们发现，DLK和LZK的诱导神经元缺失，但并非单独使用激酶，可以废除PTEN缺失诱导的CST轴突的再生和发芽，并减少损伤后自然呈现的轴突芽。因此，DLK/LZK介导的损伤信号不仅在受伤的神经元中起作用以调节再生，而且在未受伤的神经元中出乎意料地调节发芽。删除DLK和LZK不会干扰PTEN/MTOR信号传导，这表明损伤信号传导和再生能力是独立控制的。这些数据与我们先前的研究有关星形胶质反应性和疤痕的形成，这些数据说明了这对MAP3K在神经元和神经元中的多细胞功能在哺乳动物脊髓的损伤反应中。

SIGNIFICANCE STATEMENTFunctional recovery after spinal cord injury is limited because of a lack of axonal repair in the mammalian CNS. Dual leucine-zipper kinase (DLK) and leucine zipper kinase (LZK) are two closely related protein kinases that have emerged as regulators of neuronal responses to injury. However, their role in axonal repair in the mammalian spinal cord has not been described. Here, we show that DLK and LZK together play critical roles in axonal repair in the mammalian spinal cord, validating them as potential targets to promote repair and recovery after spinal cord injury. In addition to regulating axonal regeneration from injured neurons, both kinases also regulate compensatory axonal growth from uninjured neurons, indicating a more pervasive role in CNS repair than originally anticipated.