ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
SkpA restrains synaptic terminal growth during development and promotes axonal degeneration following injury.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 42 citations in OpenAlex.
- The Repair Manual of a Fruit Fly Brain.International journal of molecular sciences · 2026Review
- A nerve-wracking buzz: lessons fromFrontiers in aging neuroscience · 2023Review
- Distinct developmental and degenerative functions of SARM1 require NAD+ hydrolase activity.PLoS genetics · 2022Article
- Insights into nervous system repair from the fruit fly.Neuronal signaling · 2022Review
- SARM1 can be a potential therapeutic target for spinal cord injury.Cellular and molecular life sciences : CMLS · 2022Review
- Protein phosphatase 2A restrains DLK signaling to promote proper Drosophila synaptic development and mammalian cortical neuron survival.Neurobiology of disease · 2022Article
- The Ubiquitinated Axon: Local Control of Axon Development and Function by Ubiquitin.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Review
- The SARM1 axon degeneration pathway: control of the NADCurrent opinion in neurobiology · 2020Review
- Programmed axon degeneration: from mouse to mechanism to medicine.Nature reviews. Neuroscience · 2020Review
- Bidirectional Regulation of Sleep and Synapse Pruning after Neural Injury.Current biology : CB · 2020Article
- Structural and Functional Plasticity in the Regenerating Olfactory System of the Migratory Locust.Frontiers in physiology · 2020Review
- Wnd/DLK Is a Critical Target of FMRP Responsible for Neurodevelopmental and Behavior Defects in the Drosophila Model of Fragile X Syndrome.Cell reports · 2019Article
- Mechanisms of injury-induced axon degeneration.Current opinion in neurobiology · 2019Review
- Review
- The E3 ligase Highwire promotes synaptic transmission by targeting the NAD-synthesizing enzyme dNmnat.EMBO reports · 2019Article
- An axonal stress response pathway: degenerative and regenerative signaling by DLK.Current opinion in neurobiology · 2018Review
- HSP90 is a chaperone for DLK and is required for axon injury signaling.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Palmitoylation enables MAPK-dependent proteostasis of axon survival factors.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2.The Journal of biological chemistry · 2018Article
- Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The Wallenda (Wnd)/dual leucine zipper kinase (DLK)-Jnk pathway is an evolutionarily conserved MAPK signaling pathway that functions during neuronal development and following axonal injury. Improper pathway activation causes defects in axonal guidance and synaptic growth, whereas loss-of-function mutations in pathway components impairs axonal regeneration and degeneration after injury. Regulation of this pathway is in part through the E3 ubiquitin ligase Highwire (Hiw), which targets Wnd/DLK for degradation to limit MAPK signaling. To explore mechanisms controlling Wnd/DLK signaling, we performed a large-scale genetic screen in Drosophila to identify negative regulators of the pathway. Here we describe the identification and characterization of SkpA, a core component of SCF E3 ubiquitin ligases. Mutants in SkpA display synaptic overgrowth and an increase in Jnk signaling, similar to hiw mutants. The combination of hypomorphic alleles of SkpA and hiw leads to enhanced synaptic growth. Mutants in the Wnd-Jnk pathway suppress the overgrowth of SkpA mutants demonstrating that the synaptic overgrowth is due to increased Jnk signaling. These findings support the model that SkpA and the E3 ligase Hiw function as part of an SCF-like complex that attenuates Wnd/DLK signaling. In addition, SkpA, like Hiw, is required for synaptic and axonal responses to injury. Synapses in SkpA mutants are more stable following genetic or traumatic axonal injury, and axon loss is delayed in SkpA mutants after nerve crush. As in highwire mutants, this axonal protection requires Nmnat. Hence, SkpA is a novel negative regulator of the Wnd-Jnk pathway that functions with Hiw to regulate both synaptic development and axonal maintenance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.