Role of dual leucine zipper-bearing kinase (DLK/MUK/ZPK) in axonal growth.
In developing cerebral cortices, post-mitotic neurons migrate toward the pial surface, elongating their axons concurrently. It has been reported that targeted-deletion of the dual leucine zipper-bearing kinase (DLK)/mitogen-activated protein kinase upstream protein kinase (MUK)/leucine-zipper protein kinase (ZPK) gene, which encodes a MAP kinase kinase kinase (MAPKKK) for c-Jun N-terminal kinase (JNK), leads to a neuronal migration-defect and hypoplasia of axonal fiber tracts including those of the anterior commissure and corpus callosum. However, there is no evidence that DLK directly regulates axonal development, because another possibility, i.e. that the defective axonal development in the DLK mutant might be caused secondary to migration failure cannot be ruled out. In this study, we first examined the distributions of DLK mRNA and its protein in the developing cerebral cortex, and found that major portion of DLK proteins appear to be transported into axons. Using dissociated cortical neurons and PC12 cells, we provide direct evidence that DLK regulates axonal elongation. Furthermore, knock-down of DLK decreased the phosphorylation of JNK and its substrate, microtubule-associated protein 1B (MAP1B), which is known to be involved in axonal elongation. These results suggest that the DLK/MUK/ZPK-JNK pathway directly regulates axonal growth through phosphorylation of MAP1B.
Eto
Kaoru
K
Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Kawauchi
Takeshi
T
Osawa
Makiko
M
Tabata
Hidenori
H
Nakajima
Kazunori
K
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001369:Axons / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D064550:Death-Associated Protein Kinases; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014162:Transfection / Q000379:methods
D051017:Apoptosis Regulatory Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; C085284:microtubule-associated protein 1B; D049452:Green Fluorescent Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020930:MAP Kinase Kinase Kinases; C109162:MAP3K13 protein, human; D048670:MAP Kinase Kinase 4