title: Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons.
abstract: 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 Wldsand 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.
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Kanchana K
authors.initials: KK
authors.lastname: Gamage
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Cheng
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Park
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Mardeen S
authors.initials: MS
authors.lastname: Karim
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Kazusa
authors.initials: K
authors.lastname: Edamura
authors.affiliation: Department of Physics and Astronomy, James Madison University, Harrisonburg, VA 22807, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hughes
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Spano
authors.affiliation: Department of Psychology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Alev
authors.initials: A
authors.lastname: Erisir
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA. Electronic address: deppmann@virginia.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Deppmann
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D019771:Axotomy; D051379:Mice; D009186:Myelin Sheath / Q000473:pathology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D014855:Wallerian Degeneration / Q000235:genetics* / Q000473:pathology
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse
keywords: DR6; NGF deprivation; Wallerian degeneration; axotomy