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: 6.75). 12/2006; 26(46):11992-2002. DOI: 10.1523/JNEUROSCI.2272-06.2006
Source: PubMed

ABSTRACT 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.
    Journal of Experimental Medicine 10/2013; 210(12). DOI:10.1084/jem.20122832 · 13.91 Impact Factor
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    • "Dual leucine zipper kinase (DLK) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that can activate cJun N-terminal kinases (JNK) and p38 MAPK (Fan et al., 1996). In addition to its role for neural development (Bloom et al., 2007; Hirai et al., 2006; Itoh et al., 2011), DLK is involved in injury responses such as axon degeneration and neuronal apoptosis (Chen et al., 2008; Ghosh et al., 2011; Miller et al., 2009; Xiong and Collins, 2012). Moreover, recent studies in C. elegans and Drosophila have demonstrated that DLK is required for the regenerative response after axotomy; in the absence of DLK, reformation of a growth cone from the severed stump is disrupted (Hammarlund et al., 2009; Xiong et al., 2010; Yan et al., 2009), while in juvenile DLK gene-trap mice, there is less regrowth of axons from dissected and cultured dorsal root ganglion (DRG) explants (Itoh et al., 2009). "
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    ABSTRACT: Here we demonstrate that the dual leucine zipper kinase (DLK) promotes robust regeneration of peripheral axons after nerve injury in mice. Peripheral axon regeneration is accelerated by prior injury; however, DLK KO neurons do not respond to a preconditioning lesion with enhanced regeneration in vivo or in vitro. Assays for activation of transcription factors in injury-induced proregenerative pathways reveal that loss of DLK abolishes upregulation of p-STAT3 and p-cJun in the cell body after axonal injury. DLK is not required for the phosphorylation of STAT3 at the site of nerve injury but is necessary for retrograde transport of p-STAT3 to the cell body. These data demonstrate that DLK enhances regeneration by promoting a retrograde injury signal that is required for the activation of the neuronal proregenerative program.
    Neuron 06/2012; 74(6):1015-22. DOI:10.1016/j.neuron.2012.04.028 · 15.98 Impact Factor
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    • "DLK, like JNK, is predominantly expressed in the IZ (Hirai et al., 2002; Kawauchi et al., 2003). Overexpression of DLK perturbs radial migration (Hirai et al., 2002), and genetic disruption of DLK decreases JNK activity and the phosphorylation of known JNK substrates, including c-Jun and DCX, and impairs axon growth and radial migration of neocortical pyramidal neurons (Hirai et al., 2006). As mentioned above, MEKK4/MAP3K4 is also associated with migration defects and links JNK with Filamin A (Sarkisian et al., 2006). "
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    ABSTRACT: The architectonics of the mammalian brain arise from a remarkable range of directed cell migrations, which orchestrate the emergence of cortical neuronal layers and pattern brain circuitry. At different stages of cortical histogenesis, specific modes of cell motility are essential to the stepwise formation of cortical architecture. These movements range from interkinetic nuclear movements in the ventricular zone, to migrations of early-born, postmitotic polymorphic cells into the preplate, to the radial migration of precursors of cortical output neurons across the thickening cortical wall, and the vast, tangential migrations of interneurons from the basal forebrain into the emerging cortical layers. In all cases, actomyosin motors act in concert with cell adhesion receptor systems to provide the force and traction needed for forward movement. As key regulators of actin and microtubule cytoskeletons, cell polarity, and adhesion, the Rho GTPases play critical roles in CNS neuronal migration. This review will focus on the different types of migration in the developing neocortex and cerebellar cortex, and the role of the Rho GTPases, their regulators and effectors in these CNS migrations, with particular emphasis on their involvement in radial migration.
    Developmental Neurobiology 06/2011; 71(6):528-53. DOI:10.1002/dneu.20850 · 4.19 Impact Factor
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