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The Journal of Neuroscience, November 15, 2006, 26(46):11992-12002; doi:10.1523/JNEUROSCI.2272-06.2006

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

Syu-ichi Hirai,¹ De Feng Cui,¹ Takaki Miyata,² Masaharu Ogawa,³ Hiroshi Kiyonari,⁴ Yoko Suda,⁵ Shinichi Aizawa,⁵ Yumi Banba,¹ and Shigeo Ohno¹

¹Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama 236-0004, Japan, ²Department of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan, ³Laboratory for Cell Culture Development, Brain Science Institute, RIKEN, Saitama 351-0198, Japan, and ⁴Laboratories for Animal Resources and Genetic Engineering and ⁵Vertebrate Body Plan, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan

Correspondence should be addressed to Syu-ichi Hirai, Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. Email: sh3312{at}med.yokohama-cu.ac.jp

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.

Key words: cerebral cortex; axon; migration; pyramidal cell; c-Jun; microtubules

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Received May 29, 2006; revised Oct. 6, 2006; accepted Oct. 6, 2006.

Correspondence should be addressed to Syu-ichi Hirai, Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. Email: sh3312{at}med.yokohama-cu.ac.jp

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