The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex.
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.
Hirai
Syu-ichi
S
Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama 236-0004, Japan. sh3312@med.yokohama-cu.ac.jp
Cui
De Feng
DF
Miyata
Takaki
T
Ogawa
Masaharu
M
Kiyonari
Hiroshi
H
Suda
Yoko
Y
Aizawa
Shinichi
S
Banba
Yumi
Y
Ohno
Shigeo
S
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000201:enzymology*; D002678:Chimera; D000089622:Doublecortin Domain Proteins; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020439:Growth Cones / Q000201:enzymology* / Q000648:ultrastructure; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D009479:Neuropeptides / Q000378:metabolism; D009924:Organ Culture Techniques; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000201:enzymology
D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12