Department of Neurology, School of Medicine and Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817,
Department of Neurology, School of Medicine and Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817.
J Neurosci. 2014 Aug 6;34(32):10729-42. doi: 10.1523/JNEUROSCI.0539-14.2014.
Motoneuron death after transection of the axons (axotomy) in neonates is believed to share the same mechanistic bases as naturally occurring programmed cell death during development. The c-Jun N-terminal kinase pathway is activated in both forms of motoneuron death, but it remains unknown to what extent these two forms of motoneuron death depend on this pathway and which upstream kinases are involved. We found that numbers of facial motoneurons are doubled in neonatal mice deficient in either ZPK/DLK (zipper protein kinase, also known as dual leucine zipper kinase), a mitogen-activated protein kinase kinase kinase, or in MKK4/MAP2K4, a mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, and that the facial motoneurons in those mutant mice are completely resistant to axotomy-induced death. Conditional deletion of MKK4/MAP2K4 in neurons further suggested that ZPK/DLK and MKK4/MAP2K4-dependent mechanisms underlying axotomy-induced death are motoneuron autonomous. Nevertheless, quantitative analysis of facial motoneurons during embryogenesis revealed that both ZPK/DLK and MKK4/MAP2K4-dependent and -independent mechanisms contribute to developmental elimination of excess motoneurons. In contrast to MKK4/MAP2K4, mice lacking MKK7/MAP2K7, another mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, conditionally in neurons did not have excess facial motoneurons. However, some MKK7/MAP2K7-deficient facial motoneurons were resistant to axotomy-induced death, indicating a synergistic effect of MKK7/MAP2K7 on axotomy-induced death of these facial motoneurons. Together, our study provides compelling evidence for the pivotal roles of the ZPK/DLK and MKK4/MAP2K4-dependent mechanism in axotomy-induced motoneuron death in neonates and also demonstrates that axotomy-induced motoneuron death is not identical to developmental motoneuron death with respect to the involvement of ZPK/DLK, MKK4/MAP2K4 and MKK7/MAP2K7.
轴突横断（轴突切断）后新生动物运动神经元的死亡被认为与发育过程中自然发生的程序性细胞死亡具有相同的机制基础。c-Jun N 端激酶途径在这两种运动神经元死亡中都被激活，但尚不清楚这两种运动神经元死亡在多大程度上依赖于该途径，以及涉及哪些上游激酶。我们发现，在缺乏丝裂原活化蛋白激酶激酶激酶（也称为双亮氨酸拉链激酶）ZPK/DLK 或其直接下游丝裂原活化蛋白激酶激酶 MKK4/MAP2K4 的新生小鼠中，面部运动神经元的数量增加了一倍，并且这些突变小鼠中的面部运动神经元完全抵抗轴突切断诱导的死亡。神经元中 MKK4/MAP2K4 的条件性缺失进一步表明，ZPK/DLK 和 MKK4/MAP2K4 依赖性机制是轴突切断诱导死亡的运动神经元自主的。然而，在胚胎发生过程中对面部运动神经元的定量分析表明，ZPK/DLK 和 MKK4/MAP2K4 依赖性和非依赖性机制都有助于过量运动神经元的发育消除。与 MKK4/MAP2K4 相反，条件性地在神经元中缺失另一种丝裂原活化蛋白激酶激酶 MKK7/MAP2K7（也称为双亮氨酸拉链激酶）的小鼠没有多余的面部运动神经元。然而，一些 MKK7/MAP2K7 缺陷的面部运动神经元对轴突切断诱导的死亡有抗性，表明 MKK7/MAP2K7 对这些面部运动神经元的轴突切断诱导死亡具有协同作用。总之，我们的研究为 ZPK/DLK 和 MKK4/MAP2K4 依赖性机制在新生动物轴突切断诱导的运动神经元死亡中的关键作用提供了有力的证据，并且还表明，就 ZPK/DLK、MKK4/MAP2K4 和 MKK7/MAP2K7 的参与而言，轴突切断诱导的运动神经元死亡与发育中的运动神经元死亡并不完全相同。
