Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons

Curr Biol. 2017 Mar 20;27(6):890-896. doi: 10.1016/j.cub.2017.01.062. Epub 2017 Mar 9.


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.

Keywords: DR6; NGF deprivation; Wallerian degeneration; axotomy.

MeSH terms

  • Animals
  • Axons / pathology*
  • Axotomy
  • Mice
  • Myelin Sheath / pathology*
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / metabolism
  • Wallerian Degeneration / genetics*
  • Wallerian Degeneration / pathology


  • Receptors, Tumor Necrosis Factor
  • Tnfrsf21 protein, mouse