Article

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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    • "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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    • "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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