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リエゾンラボ研究会
発表内容

Title:
Molecular and cellular mechanisms for the radial glial fiber-dependent locomotion mode of cortical neuronal migration

Takeshi Kawauchi, Ph.D.
Department of Anatomy, Keio University School of Medicine
PRESTO, JST

Abstract:
Proper regulation of cell migration is essential for various biological events, including the development of nervous system. During the development of cerebral cortex, the migration of neurons plays important roles in cortical layer formation and brain function, as migration defects result in neurological disorders such as mental retardation and epilepsy. Neurons, generated near the ventricle, exhibit various morphological changes, and subsequently they form a leading process and migrate over a long distance along radial glial fibers. This long-distance neuronal migration, called the locomotion mode of migration, 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. We established an ex vivo chemical inhibitor screening method, allowing us to directly analyze the locomotion mode of migration, and found that Cdk5 is involved in the regulation of nuclear morphological changes and migration in the locomoting neurons. Together with our previous findings that Cdk5 has essential roles at the early phase of neuronal migration, our data suggest that Cdk5 differentially regulates several steps for neuronal migration. We also found that a cell-cell adhesion molecule, N-Cadherin, is expressed in migrating neurons and radial glial fibers and required for proper neuronal migration. Furthermore, we revealed that the intracellular trafficking of N-Cadherin via Rab5-dependent endocytosis and Rab11-dependent recycling pathway is essential for the neuronal migration along the radial glial fibers. These data uncovered the molecular and cellular mechanisms for the radial glial fiber-dependent locomotion mode of neuronal migration during the development of cerebral cortex. Our findings also shed light on the physiological roles for endocytic pathways in cell migration.

References:
1. Kawauchi T, Sekine K, Shikanai M, Chihama K, Tomita K, Kubo K, Nakajima K, Nabeshima YI, Hoshino M. “ Rab GTPases-dependent endocytic pathways regulate neuronal migration and maturation through N-Cadherin trafficking” Neuron (2010) 67, 588-602.

2. Nishimura YV, Sekine K, Chihama K, Nakajima K, Hoshino M, Nabeshima YI, Kawauchi T. “Dissecting the factors involved in the locomotion mode of neuronal migration in the developing cerebral cortex” J Biol Chem (2010) 285, 5878-5887.

3. Kawauchi T, Chihama K, Nabeshima YI, Hoshino M “Cdk5 phosphorylates and stabilizes p27 kip1 contributing to actin organization and cortical neuronal migration” Nature Cell Biol (2006) 8, 17-26.

4. Kawauchi T, Chihama K, Nabeshima YI, Hoshino M “The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration” EMBO J (2003) 22, 4190-4201.