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; De Feng Cui; Takaki Miyata; Masaharu Ogawa; Hiroshi Kiyonari; Yoko Suda; Shinichi Aizawa; Yumi Banba; Shigeo Ohno

doi:10.1523/JNEUROSCI.2272-06.2006

The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex

J Neurosci. 2006 Nov 15;26(46):11992-2002. doi: 10.1523/JNEUROSCI.2272-06.2006.

Authors

Syu-ichi Hirai¹, De Feng Cui, Takaki Miyata, Masaharu Ogawa, Hiroshi Kiyonari, Yoko Suda, Shinichi Aizawa, Yumi Banba, Shigeo Ohno

Affiliation

¹ Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama 236-0004, Japan. [email protected]

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology
Cell Movement / physiology*
Cerebral Cortex / cytology
Cerebral Cortex / embryology*
Cerebral Cortex / enzymology*
Chimera
Doublecortin Domain Proteins
Enzyme Activation / physiology
Enzyme Inhibitors / pharmacology
Female
Growth Cones / enzymology*
Growth Cones / ultrastructure
JNK Mitogen-Activated Protein Kinases / metabolism*
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Inbred ICR
Mice, Knockout
Microtubule-Associated Proteins / metabolism
Neural Pathways / cytology
Neural Pathways / embryology
Neural Pathways / enzymology
Neuropeptides / metabolism
Organ Culture Techniques
Proto-Oncogene Proteins c-jun / metabolism
Pyramidal Cells / cytology
Pyramidal Cells / enzymology

Substances

Doublecortin Domain Proteins
Enzyme Inhibitors
Microtubule-Associated Proteins
Neuropeptides
Proto-Oncogene Proteins c-jun
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinases
mitogen-activated protein kinase kinase kinase 12