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Degeneration of Injured Axons and Dendrites Requires Restraint of a Protective JNK Signaling Pathway by the Transmembrane Protein Raw.

Authors
  • Hao, Yan1
  • Waller, Thomas J1
  • Nye, Derek M2
  • Li, Jiaxing1
  • Zhang, Yanxiao3
  • Hume, Richard I1
  • Rolls, Melissa M2
  • Collins, Catherine A4
  • 1 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1085.
  • 2 Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, and.
  • 3 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109-2218.
  • 4 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1085, [email protected]
Type
Published Article
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Publication Date
Oct 23, 2019
Volume
39
Issue
43
Pages
8457–8470
Identifiers
DOI: 10.1523/JNEUROSCI.0016-19.2019
PMID: 31492772
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The degeneration of injured axons involves a self-destruction pathway whose components and mechanism are not fully understood. Here, we report a new regulator of axonal resilience. The transmembrane protein Raw is cell autonomously required for the degeneration of injured axons, dendrites, and synapses in Drosophila melanogaster In both male and female raw hypomorphic mutant or knock-down larvae, the degeneration of injured axons, dendrites, and synapses from motoneurons and sensory neurons is strongly inhibited. This protection is insensitive to reduction in the levels of the NAD+ synthesis enzyme Nmnat (nicotinamide mononucleotide adenylyl transferase), but requires the c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase and the transcription factors Fos and Jun (AP-1). Although these factors were previously known to function in axonal injury signaling and regeneration, Raw's function can be genetically separated from other axonal injury responses: Raw does not modulate JNK-dependent axonal injury signaling and regenerative responses, but instead restrains a protective pathway that inhibits the degeneration of axons, dendrites, and synapses. Although protection in raw mutants requires JNK, Fos, and Jun, JNK also promotes axonal degeneration. These findings suggest the existence of multiple independent pathways that share modulation by JNK, Fos, and Jun that influence how axons respond to stress and injury.SIGNIFICANCE STATEMENT Axonal degeneration is a major feature of neuropathies and nerve injuries and occurs via a cell autonomous self-destruction pathway whose mechanism is poorly understood. This study reports the identification of a new regulator of axonal degeneration: the transmembrane protein Raw. Raw regulates a cell autonomous nuclear signaling pathway whose yet unknown downstream effectors protect injured axons, dendrites, and synapses from degenerating. These findings imply that the susceptibility of axons to degeneration is strongly regulated in neurons. Future understanding of the cellular pathway regulated by Raw, which engages the c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase and Fos and Jun transcription factors, may suggest new strategies to increase the resiliency of axons in debilitating neuropathies. Copyright © 2019 the authors.

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