ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
ZPK/DLK and MKK4 form the critical gateway to axotomy-induced motoneuron death in neonates.
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 18 papers.
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Who cites it
18 citing papers in PubMed, 21 citations in OpenAlex.
- Loss of Sarm1 Mitigates Axonal Degeneration and Promotes Neuronal Repair After Ischemic Stroke.bioRxiv : the preprint server for biology · 2025Article
- Remyelination protects neurons from DLK-mediated neurodegeneration.Nature communications · 2024Article
- Remyelination protects neurons from DLK-mediated neurodegeneration.bioRxiv : the preprint server for biology · 2024Article
- The response of Dual-leucine zipper kinase (DLK) to nocodazole: Evidence for a homeostatic cytoskeletal repair mechanism.PloS one · 2024Article
- Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Review
- Palmitoylation couples the kinases DLK and JNK3 to facilitate prodegenerative axon-to-soma signaling.Science signaling · 2022Article
- Article
- Axon injury signaling and compartmentalized injury response in glaucoma.Progress in retinal and eye research · 2019Review
- Multitasking: Dual Leucine Zipper-Bearing Kinases in Neuronal Development and Stress Management.Annual review of cell and developmental biology · 2019Review
- Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun signaling.Human molecular genetics · 2019Article
- Apoptotic cell death regulation in neurons.The FEBS journal · 2019Review
- DLK regulates a distinctive transcriptional regeneration program after peripheral nerve injury.Neurobiology of disease · 2019Article
- Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury.eLife · 2018Article
- DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats.Neurobiology of disease · 2017Article
- Article
- Leucine Zipper-bearing Kinase promotes axon growth in mammalian central nervous system neurons.Scientific reports · 2016Article
- Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Motoneuron death after transection of the axons (axotomy) in neonates is believed to share the same mechanistic bases as naturally occurring programmed cell death during development. The c-Jun N-terminal kinase pathway is activated in both forms of motoneuron death, but it remains unknown to what extent these two forms of motoneuron death depend on this pathway and which upstream kinases are involved. We found that numbers of facial motoneurons are doubled in neonatal mice deficient in either ZPK/DLK (zipper protein kinase, also known as dual leucine zipper kinase), a mitogen-activated protein kinase kinase kinase, or in MKK4/MAP2K4, a mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, and that the facial motoneurons in those mutant mice are completely resistant to axotomy-induced death. Conditional deletion of MKK4/MAP2K4 in neurons further suggested that ZPK/DLK and MKK4/MAP2K4-dependent mechanisms underlying axotomy-induced death are motoneuron autonomous. Nevertheless, quantitative analysis of facial motoneurons during embryogenesis revealed that both ZPK/DLK and MKK4/MAP2K4-dependent and -independent mechanisms contribute to developmental elimination of excess motoneurons. In contrast to MKK4/MAP2K4, mice lacking MKK7/MAP2K7, another mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, conditionally in neurons did not have excess facial motoneurons. However, some MKK7/MAP2K7-deficient facial motoneurons were resistant to axotomy-induced death, indicating a synergistic effect of MKK7/MAP2K7 on axotomy-induced death of these facial motoneurons. Together, our study provides compelling evidence for the pivotal roles of the ZPK/DLK and MKK4/MAP2K4-dependent mechanism in axotomy-induced motoneuron death in neonates and also demonstrates that axotomy-induced motoneuron death is not identical to developmental motoneuron death with respect to the involvement of ZPK/DLK, MKK4/MAP2K4 and MKK7/MAP2K7.
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