DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity
Open accessAbstract
The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo.
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A pathway involving DLK, JNK, and PERK has previously been implicated in neuronal death.
“A pathway involving DLK, JNK and PERK has previously been implicated in neuronal death (Ghosh et al., 2011; Huntwork-Rodriguez et al., 2013; Larhammar et al., 2017; Miller et al., 2009; Pozniak et al., 2013; Watkins et al., 2013; Welsbie et al., 2013), validating our approach.”
From CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons (2019) · cites this paper as Ghosh et al., 2011
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- Authors
- Sengupta Ghosh, A., Wang, B., Pozniak, C. D., Chen, M., Watts, R. J., & Lewcock, J. W.
- Affiliations
- Neurodegeneration Laboratories, Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080
- Genentech (US)
- Corresponding author
- Lewcock, Joseph W.
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2011-09-05
- Volume
- 194
- Issue
- 5
- Pages
- 751-764
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3171129
- OpenAlex
- W2119009867
- Cited by
- 220
- References
- 54
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 25 · 2023: 10 · 2022: 14 · 2021: 13 · 2020: 11 · 2019: 20 · 2018: 20 · 2017: 19 · 2016: 16 · 2015: 8 · 2014: 11 · 2013: 17 · 2012: 9
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- DLK, JNK signaling, neuronal apoptosis, axonal degeneration, JIP3, c-Jun phosphorylation, neuronal homeostasis
- MeSH terms
- Animals, Axons, Cells, Cultured, Central Nervous System, Embryo, Mammalian, Ganglia, Spinal, Mice, Inbred Strains, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Phosphorylation, Protein Binding, Spinal Cord, Transcription Factors, Proto-Oncogene Proteins c-jun, Apoptosis, Mice, Knockout, Homeodomain Proteins, MAP Kinase Kinase Kinases, Nerve Growth Factor, Protein Transport, RNA, Small Interfering, Protein Kinase Inhibitors, JNK Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Mice, Caspase 3, Caspase 9
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