| First Author | Gamage KK | Year | 2017 |
| Journal | Curr Biol | Volume | 27 |
| Issue | 6 | Pages | 890-896 |
| PubMed ID | 28285993 | Mgi Jnum | J:321824 |
| Mgi Id | MGI:6856155 | Doi | 10.1016/j.cub.2017.01.062 |
| Citation | Gamage KK, et al. (2017) Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons. Curr Biol 27(6):890-896 |
| abstractText | 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 in Wld(s) and Sarm1(-/-) mice, preserved axons in DR6(-/-) 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. |
