Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons

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 Wlds 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. [Display omitted] •DR6 has a modest role in developmental axon degeneration•DR6 is required for Wallerian degeneration in vitro and in vivo•Axon degeneration and demyelination can be mechanistically uncoupled post-injury•DR6 is required for the activation of classic Wallerian degeneration pathways TNFR family members contribute to axon degeneration during development, but receptors have not been identified for Wallerian degeneration. Gamage et al. show that death receptor 6 is required for injury-induced nerve degeneration. This is the first report of a receptor capable of promoting axon degeneration after injury.