The c-Jun N-Terminal Kinase Activator Dual Leucine Zipper Kinase Regulates Axon Growth and Neuronal Migration in the Developing Cerebral Cortex

Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama 236-0004, Japan.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2006; 26(46):11992-2002. DOI: 10.1523/JNEUROSCI.2272-06.2006
Source: PubMed


Mammalian corticogenesis substantially depends on migration and axon projection of newborn neurons that are coordinated by a yet unidentified molecular mechanism. Dual leucine zipper kinase (DLK) induces activation of c-Jun N-terminal kinase (JNK), a molecule that regulates morphogenesis in various organisms. We show here, using gene targeting in mice, that DLK is indispensable for establishing axon tracts, especially those originating from neocortical pyramidal neurons of the cerebrum. Direct and quantitative analysis of radial migration of pyramidal neurons using slice culture and a time-lapse imaging system revealed that acceleration around the subplate was affected by DLK gene disruption and by administration of a JNK inhibitor. Phosphorylation of JNK substrates, including c-Jun and doublecortin, and of JNK itself at the activation loop were partially affected in brains of DLK-deficient mouse embryos. These data suggest that DLK plays a significant role in the coordinated regulation of radial migration and axon projection by modulating JNK activity.

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    • "Consistent with these findings, observation of DLK lox ;Cre pos animals for 3 mo after Tamoxifen treatment revealed no changes in body weight or decreased viability as a result of the reduced DLK expression. Together, these data suggest that deletion of DLK in the adult brain does not result in similar phenotypes to those observed in germline DLK-null animals (Hirai et al., 2006). "
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    ABSTRACT: Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid-induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.
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    • "Previous studies show severe impairments on dendritic structure in the cerebellum and motor cortex of c-Jun N-terminal kinase 1 (JNK1)-deficient mice [34]. JNKs may influence cytoskeletal reorganization via the phosphorylation of proteins regulating microtubule stability, including doublecortin (DCX), stathmin family protein (SCG10), and microtubule- associated proteins, MAP2 and MAP1B [34], [50]. "
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    Full-text · Article · May 2013 · PLoS ONE
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    • "The following antibodies were used: anti-JIP1 mAb (TDL), anti-JIP1 pAb (Zymed), anti-KHC mAb (Chemicon), anti-JIP3 pAb (Santa Cruz), anti-DLK pAb (described previously [33]), anti-JNK1 mAb (BD Biosciences Pharmingen), anti-JNK2 mAb (Santa Cruz), anti-GFP mAb (Santa Cruz), anti-GFP pAb (MBL), anti-RFP pAb (Clontech), anti-V5 mAb (Invitrogen), anti-SBP mAb for TAP-tagged proteins (Santa Cruz), anti-Omni mAb for T7-DLK (Santa Cruz), HRP-conjugated anti-rabbit IgG and anti-mouse IgG (GE Healthcare), HRP-conjugated anti-goat IgG (Zymed). "
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