Death receptor 6 does not regulate axon degeneration and Schwann cell injury responses during Wallerian degeneration.

Overview

1. Department of Neurology, The Neuroscience Research Institute, College of Medicine, The Ohio State University Wexner Medical Center Columbus United States

Abstract

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, encoded by 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• doi:10.5061/dryad.g79cnp652, at Dryad; found in “Data availability”

Data availability

Numerical source data and raw western blot data have been provided for all figures in this article. The electron microscopy, immunofluorescence, and phase contrast raw imaging datasets have been deposited at Dryad (https://doi.org/10.5061/dryad.g79cnp652) and are publicly available.

The following dataset was generated:

BeirowskiB HuangH BabetteE Dryad Digital Repository2026Data from: Death receptor 6 does not regulate axon degeneration and Schwann cell injury responses during Wallerian degeneration10.5061/dryad.g79cnp652PMC1303088941891813

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 3 authors, 5 keywords, 7 MeSH terms, 1 funder, 44 references.

Cite

This paper

Beirowski, B., Huang, H., & Babetto, E. (2026). Death receptor 6 does not regulate axon degeneration and Schwann cell injury responses during Wallerian degeneration. eLife, 14, RP108389. https://doi.org/10.7554/elife.108389

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