In the developing cerebral cortex, a cohort of neural progenitors, located near the ventricle, differentiates into neurons and exhibits multi-step migration toward the pial surface. Defects in neuronal differentiation and migration cause several neurological disorders, such as lissencephaly and microcephaly. We and others have previously reported that Cyclin-dependent kinase-5 (Cdk5) play multiple roles in neuronal differentiation and multi-step neuronal migration (reviewed in Kawauchi T. (2014) Dev Growth Differ). We reported that Cdk5 and its substrate, p27^kip1, regulate multipolar process formation of neurons at the early phase of migration through actin reorganization (Nature Cell Biol, 2006). We also found that Cdk5 is required for the locomotion mode of neuronal migration, which covers most part of migration path (J Biol Chem, 2010). However, downstream events of Cdk5 in the locomoting neurons were still unclear. Our recent data indicate that Cdk5 are required for the formation of a cytoplasmic dilation, a migrating neuron-specific structure found at the proximal region of a leading process. We also found that Cdk5 controls endocytic trafficking as well as microtubule organization, and pharmacological inhibition of endocytosis or microtubule polymerization disturbs the cytoplasmic dilation formation and locomotion mode of neuronal migration. In this symposium, I will also introduce the Cdk5 substrate involved in the dilation formation during the locomotion mode of neuronal migration.