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Morphological and Functional Evaluation of Axons and their Synapses during Axon Death in Drosophila melanogaster
Published on: March 16, 2020
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Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons
Kanchana K Gamage1, Irene Cheng2, Rachel E Park1
1Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
Current Biology : CB
|March 14, 2017
Summary
Death receptor 6 (DR6) drives axon degeneration after nerve injury. DR6 deficiency preserves axons and myelin, revealing distinct degeneration pathways and linking extrinsic DR6 signaling to intrinsic mechanisms.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Axon degeneration is crucial for nervous system development and pathological conditions like nerve injury.
- Distinct molecular mechanisms underlie developmental (extrinsic) and pathological (intrinsic) axon degeneration.
- Receptors were not previously implicated in Wallerian degeneration, the primary form of pathological axon disintegration.
Purpose of the Study:
- To investigate the role of tumor necrosis factor receptor superfamily (TNFRSF) members in Wallerian degeneration.
- To determine if the orphan receptor, death receptor 6 (DR6), contributes to axon degeneration after injury.
- To elucidate the relationship between DR6 signaling and established intrinsic axon degeneration pathways.
Main Methods:
- Utilized microfluidic devices to culture sympathetic and sensory neurons for in vitro axotomy experiments.
- Employed DR6 knockout (DR6-/-) mice to validate in vitro findings in an in vivo transected sciatic nerve model.
- Analyzed axon and myelin integrity post-injury and investigated JNK signaling pathways.
Main Results:
- DR6 was found to be essential for driving axon degeneration following axotomy in vitro.
- DR6-/- mice exhibited significantly preserved axons for up to 4 weeks after sciatic nerve injury.
- Axons in DR6-/- mice showed distinct myelin remodeling, indicating separate axon and myelin degeneration processes.
- JNK signaling activation after injury was dependent on DR6.
Conclusions:
- Death receptor 6 (DR6) plays a critical role in mediating pathological axon degeneration after nerve injury.
- DR6-dependent axon degeneration is mechanistically distinct from myelin deterioration.
- DR6 represents a novel extrinsic pathway that interacts with intrinsic mechanisms in Wallerian degeneration.
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