Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons.
Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons.
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DOI：
10.1016/j.cub.2017.01.062
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发表时间：
2017-03-20
期刊：
影响因子：
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通讯作者：
Deppmann CD
中科院分区：
文献类型：
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作者：
Gamage KK;Cheng I;Park RE;Karim MS;Edamura K;Hughes C;Spano AJ;Erisir A;Deppmann CD
发育过程中的轴突变性是塑造功能性神经系统所必需的，也是病理性损伤（如损伤）的标志[1,2]。尽管形态学特征相似，但据报道病理性和发育性变性之间的分子机制很少重叠[3-5]。在外周神经系统（PNS）中，发育轴突修剪依赖于受体介导的外源性变性机制来决定哪些轴突是维持的还是退化的[5-7]。受体与沃勒氏轴突变性无关；相反，轴突自主的内在机制被认为是这种轴突解体的主要驱动因素[8-10]。在这里，我们研究了神经表达的旁系肿瘤坏死因子受体超家族（TNFRSF）成员在Wallerian变性中的作用。我们发现，在微流体装置中培养的交感和感觉神经元中，需要一种孤儿受体，即死亡受体6 （DR6）来驱动轴突切除后的轴突变性。我们试图通过坐骨神经横切模型在体内验证这些体外发现。与体外研究结果一致，DR6−/−动物在损伤后4周仍能保存轴突。与在wldand sarm1−/−小鼠中观察到的表型相反，dr6−/−动物中保存的轴突显示出深刻的髓鞘重塑。这表明轴突和髓鞘在轴突切开术后的退化是机械上不同的过程。最后，我们发现损伤后的JNK信号需要DR6，这表明这种新的外在途径与轴突自主的内在途径之间存在联系，这种内在途径已被建立为沃勒氏变性。
Axon degeneration during development is required to sculpt a functional nervous system and is also a hallmark of pathological insult, such as injury [1, 2]. Despite similar morphological characteristics, very little overlap in molecular mechanisms has been reported between pathological and developmental degeneration [3–5]. In the peripheral nervous system (PNS), developmental axon pruning relies on receptor-mediated extrinsic degeneration mechanisms to determine which axons are maintained or degenerated [5–7]. Receptors have not been implicated in Wallerian axon degeneration; instead, axon autonomous, intrinsic mechanisms are thought to be the primary driver for this type of axon disintegration [8–10]. Here we survey the role of neuronally expressed, paralogous tumor necrosis factor receptor super family (TNFRSF) members in Wallerian degeneration. We find that an orphan receptor, death receptor 6 (DR6), is required to drive axon degeneration after axotomy in sympathetic and sensory neurons cultured in microfluidic devices. We sought to validate these in vitro findings in vivo using a transected sciatic nerve model. Consistent with the in vitro findings,DR6−/−animals displayed preserved axons up to 4 weeks after injury. In contrast to phenotypes observed inWldsandSarm1−/−mice, preserved axons inDR6−/−animals display profound myelin remodeling. This indicates that deterioration of axons and myelin after axotomy are mechanistically distinct processes. Finally, we find that JNK signaling after injury requires DR6, suggesting a link between this novel extrinsic pathway and the axon autonomous, intrinsic pathways that have become established for Wallerian degeneration.