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Axonal injury signaling is restrained by a spared synaptic branch.

Laura J Smithson | Juliana L Zang | Lucas Junginger | Thomas J Waller | Lauren Reilly-Jankowiak | Sophia A Khan | Ye Li | Dawen Cai | Catherine A Collins
eLife | 2025

The intrinsic ability of injured neurons to degenerate and regenerate their axons facilitates nervous system repair; however, this ability is not engaged in all neurons and injury locations. Here, we investigate the regulation of a conserved axonal injury response pathway with respect to the location of damage in branched motoneuron (MN) axons in Drosophila larvae. The dileucine zipper kinase (DLK; also known as MAP3K12 in mammals and Wallenda (Wnd) in Drosophila) is a key regulator of diverse responses to axonal injury. In three different populations of MNs, we observed the same striking result that Wnd/DLK signaling becomes activated only in response to injuries that remove all synaptic terminals. Injuries that spared even a small part of a synaptic terminal were insufficient to activate Wnd/DLK signaling, despite the presence of extensive axonal degeneration. The regulation of injury-induced Wnd/DLK signaling occurs independently of its previously known regulator, the Hiw/PHR ubiquitin ligase. We propose that Wnd/DLK signaling regulation is linked to the trafficking of a synapse-to-nucleus axonal cargo and that this mechanism enables neurons to respond to impairments in synaptic connectivity.

Pubmed ID: 41159443

Associated grants

  • Agency: NIH HHS, United States
    Id: P40 OD018537
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS069844
  • Agency: NINDS NIH HHS, United States
    Id: R56 NS069844
  • Agency: NIH HHS, United States
    Id: NS069844

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y[1] w[*]; P{w[+mC]=UAS-mCD8::GFP.L}LL5, P{UAS-mCD8::GFP.L}2 (organism)

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w[*]; P{w[+mW.hs]=GawB}tey[5053A]/TM6B, Tb[+] (organism)

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