Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia.
Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia.
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DOI：
10.1016/j.neuron.2020.11.012
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发表时间：
2021-02-03
期刊：
影响因子：
16.2
通讯作者：
Freeman MR
中科院分区：
文献类型：
--
作者：
Hsu JM;Kang Y;Corty MM;Mathieson D;Peters OM;Freeman MR
神经系统损伤和疾病对神经系统的功能连通性有广泛的影响，但损伤信号如何在神经回路中传播仍不清楚。在一个简单的活体神经准备中，我们探索了轴突切断如何改变被切断的轴突和邻近未受损伤的“旁观者”神经元的生理。在损伤后的几个小时内，我们观察到所有轴突的轴突运输受到抑制，无论是否损伤，以及未损伤的旁观者神经元的机械和化学感觉信号转导减少。出乎意料的是，我们发现轴突死亡分子DSARM，而不是它的NAD+水解酶活性，是旁观者神经元细胞生物学早期变化所必需的细胞自主的，就像电压门控钙通道杂音(CAC)和MAP激酶信号级联一样。旁观者神经元在随后的时间点功能恢复，而切断的轴突通过DSARM/AxunDead信号而退化，而不依赖于CAC/MAP激酶。有趣的是，旁观者神经元功能的抑制需要在胶质细胞中传递Draper/MEGF10信号，这表明胶质细胞传播损伤信号并主动抑制旁观者神经元功能。我们的工作确定了DSARM和神经胶质细胞在损伤后抑制旁观者神经元功能中的新角色，并定义了受损神经系统中DSARM信号的两个遗传和时间可分离的阶段。Hu等人的研究。证明未受损伤的旁观者神经元通过细胞自主的CAC/DSARM/MAPK信号暂时抑制其对邻近切断的轴突的生理反应，而不依赖于DSARM NADase的活性。损伤信号通过Draper介导的神经胶质细胞信号传递到旁观者神经元。他们提出了受损神经中DSARM信号的两阶段模型。
Nervous system injury and disease have broad effects on the functional connectivity of the nervous system, but how injury signals are spread across neural circuits remains unclear. We explored how axotomy changes the physiology of severed axons and adjacent uninjured “bystander” neurons in a simple in vivo nerve preparation. Within hours after injury, we observed suppression of axon transport in all axons, whether injured or not, and decreased mechano- and chemosensory signal transduction in uninjured bystander neurons. Unexpectedly, we found the axon death molecule dSarm, but not its NAD+ hydrolase activity, was required cell-autonomously for these early changes in neuronal cell biology in bystander neurons, as were the voltage-gated calcium channel Cacophony (Cac) and the MAP kinase signaling cascade. Bystander neurons functionally recovered at later time points, while severed axons degenerated via dSarm/Axundead signaling, and independently of Cac/MAP kinase. Interestingly, suppression of bystander neuron function required Draper/MEGF10 signaling in glia, indicating glial cells spread injury signals and actively suppress bystander neuron function. Our work identifies a new role for dSarm and glia in suppression of bystander neuron function after injury, and defines two genetically and temporally separable phases of dSarm signaling in the injured nervous system. Hsu et al. demonstrate that uninjured bystander neurons temporarily suppress their physiology in response to adjacent severed axons via cell-autonomous Cac/dSarm/MAPK signaling, independent of dSarm NADase activity. Injury signals are spread to bystander neurons via Draper-mediated signaling in glia. They propose a two-phase model for dSarm signaling in injured nerves.
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