Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1085.
Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, and.
J Neurosci. 2019 Oct 23;39(43):8457-8470. doi: 10.1523/JNEUROSCI.0016-19.2019. Epub 2019 Sep 6.
The degeneration of injured axons involves a self-destruction pathway whose components and mechanism are not fully understood. Here, we report a new regulator of axonal resilience. The transmembrane protein Raw is cell autonomously required for the degeneration of injured axons, dendrites, and synapses in In both male and female hypomorphic mutant or knock-down larvae, the degeneration of injured axons, dendrites, and synapses from motoneurons and sensory neurons is strongly inhibited. This protection is insensitive to reduction in the levels of the NAD synthesis enzyme Nmnat (nicotinamide mononucleotide adenylyl transferase), but requires the c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase and the transcription factors Fos and Jun (AP-1). Although these factors were previously known to function in axonal injury signaling and regeneration, Raw's function can be genetically separated from other axonal injury responses: Raw does not modulate JNK-dependent axonal injury signaling and regenerative responses, but instead restrains a protective pathway that inhibits the degeneration of axons, dendrites, and synapses. Although protection in mutants requires JNK, Fos, and Jun, JNK also promotes axonal degeneration. These findings suggest the existence of multiple independent pathways that share modulation by JNK, Fos, and Jun that influence how axons respond to stress and injury. Axonal degeneration is a major feature of neuropathies and nerve injuries and occurs via a cell autonomous self-destruction pathway whose mechanism is poorly understood. This study reports the identification of a new regulator of axonal degeneration: the transmembrane protein Raw. Raw regulates a cell autonomous nuclear signaling pathway whose yet unknown downstream effectors protect injured axons, dendrites, and synapses from degenerating. These findings imply that the susceptibility of axons to degeneration is strongly regulated in neurons. Future understanding of the cellular pathway regulated by Raw, which engages the c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase and Fos and Jun transcription factors, may suggest new strategies to increase the resiliency of axons in debilitating neuropathies.
损伤轴突的退化涉及一种自身破坏途径，其组成和机制尚未完全了解。在这里，我们报告了一种新的轴突弹性调节剂。跨膜蛋白 Raw 是自主细胞必需的，对于雄性和雌性 突变体或敲低幼虫中损伤轴突、树突和突触的退化都是必需的。从运动神经元和感觉神经元中，损伤的轴突、树突和突触的退化被强烈抑制。这种保护对 NAD 合成酶 Nmnat（烟酰胺单核苷酸腺嘌呤转移酶）水平的降低不敏感，但需要 c-Jun N 端激酶 (JNK) 有丝分裂原激活的蛋白 (MAP) 激酶和转录因子 Fos 和 Jun (AP-1)。尽管这些因子以前被认为在轴突损伤信号和再生中起作用，但 Raw 的功能可以与其他轴突损伤反应在遗传上分离：Raw 不调节 JNK 依赖性轴突损伤信号和再生反应，而是限制抑制轴突、树突和突触退化的保护途径。虽然 突变体中的保护需要 JNK、Fos 和 Jun，但 JNK 也促进轴突退化。这些发现表明存在多个独立的途径，它们共享 JNK、Fos 和 Jun 的调节，影响轴突对压力和损伤的反应方式。轴突退化是神经病变和神经损伤的主要特征，通过一种自主的自我破坏途径发生，其机制尚不清楚。本研究报告了一种新的轴突退化调节剂的鉴定：跨膜蛋白 Raw。Raw 调节自主核信号通路，其未知的下游效应物可保护损伤的轴突、树突和突触免于退化。这些发现意味着轴突对退化的易感性在神经元中受到强烈调节。对 Raw 调节的细胞通路的进一步理解，涉及 c-Jun N 端激酶 (JNK) 有丝分裂原激活的蛋白 (MAP) 激酶和 Fos 和 Jun 转录因子，可能会为增加衰弱性神经病变中轴突的弹性提供新的策略。
