Journal of Biological Chemistry
Volume 285, Issue 8, 19 February 2010, Pages 5878-5887
Journal home page for Journal of Biological Chemistry

Developmental Biology
Dissecting the Factors Involved in the Locomotion Mode of Neuronal Migration in the Developing Cerebral Cortex*

https://doi.org/10.1074/jbc.M109.033761Get rights and content
Under a Creative Commons license
open access

Neuronal migration is essential for proper cortical layer formation and brain function, because migration defects result in neurological disorders such as mental retardation and epilepsy. Neuronal migration is divided into several contiguous steps: early phase (multipolar mode), locomotion mode, and terminal translocation mode. The locomotion mode covers most of the migration route and thereby is the main contributor to cortical layer formation. However, analysis of the molecular mechanisms regulating this mode is difficult due to the secondary effects of defects at the early phase of migration. In this study, we established an ex vivo chemical inhibitor screening, allowing us to directly analyze the locomotion mode of migration. Roscovitine and PP2, inhibitors for Cdk5 and Src family kinases, respectively, suppressed the locomotion mode of migration. In line with this, a small percentage of Cdk5- or Src family kinase (Fyn)-knockdown cells exhibited locomoting morphology but retarded migration, although the majority of cells were stalled at the early phase of migration. We also showed that rottlerin, widely used as a specific inhibitor for protein kinase Cδ (PKCδ), suppressed the locomotion mode. Unexpectedly, however, the dominant-negative form as well as RNA interference for PKCδ hardly affected the locomotion, whereas they may disturb terminal translocation. In addition, we found JNK to be a potential downstream target of rottlerin. Taken together, our novel chemical inhibitor screening provides evidence that Cdk5 and Src family kinases regulate the locomotion mode of neuronal migration. It also uncovered roles for Fyn and PKCδ in the early and final phases of migration, respectively.

Cell Migration
JNK
Neurodevelopment
Protein Kinase C
Signal Transduction
Cyclin-dependent Kinase 5
Electroporation
Microtubule-associated Protein 1B
Mouse Embryonic Cerebral Cortex
Slice Culture

Cited by (0)

*

This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to M. H., T. K., Y. N., and K. N.), by grants from the Uehara Memorial Foundation (to T. K.), Takeda Science Foundation (to T. K.), Global Center of Excellence (to K. N. and T. K.), and by Keio Gijuku Academic Development Funds (to Y. V. N.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental movies 1–13 and Figs. S1 and S2.