title: DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity.
abstract: 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.
authors: Neurodegeneration Laboratories, Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA.
authors: Arundhati Sengupta
authors: AS
authors: Ghosh
authors: Bei
authors: B
authors: Wang
authors: Christine D
authors: CD
authors: Pozniak
authors: Mark
authors: M
authors: Chen
authors: Ryan J
authors: RJ
authors: Watts
authors: Joseph W
authors: JW
authors: Lewcock
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000196:embryology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000172:deficiency / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics; D021381:Protein Transport / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; C403619:Mapk8ip3 protein, mouse; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D014157:Transcription Factors; C084059:Hb9 protein, mouse; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12; D053148:Caspase 3; D053453:Caspase 9