Data from: Death receptor 6 does not regulate axon degeneration and Schwann cell injury responses during Wallerian degeneration

Axon degeneration (AxD), accompanied by glial remodeling, is a
pathological hallmark of many neurodegenerative diseases, leading to the
disruption of neuronal connectivity. Understanding the mechanisms in
neurons and glia that regulate AxD is essential for developing therapeutic
strategies to prevent or mitigate axon loss. Wallerian degeneration (WD)
is a well-established model to study the mechanisms of nerve
injury-induced AxD, glial responses, and axon-glia interactions. We
recently showed that Schwann cells (SCs), the axon-associated glia of the
peripheral nervous system, exert protective effects on axons through their
rapid metabolic injury response. Enhancing this SC response promotes axon
protection during WD. A prior study reported that eliminating the orphan
tumor necrosis factor receptor DR6 (death receptor 6, Tnfrsf21) strongly
delays AxD and alters SC injury responses during WD, suggesting a possible
intersection with our findings. Here, we rigorously revisit the role of
DR6 in WD using two independent DR6 knockout mouse lines, including the
same model used in the previous study. Surprisingly, in contrast to the
earlier report, we observed no impact of DR6 deletion on AxD kinetics or
SC injury responses across a range of WD assays. Moreover, injured axons
in primary neuronal cultures lacking DR6 degenerated at a similar rate as
wild-type axons. We conclude that DR6 is dispensable for the regulation of
AxD and glial nerve injury responses during WD. Our data argue that any
therapeutic benefit from DR6 suppression in neurodegeneration models
occurs through mechanisms independent of WD.