Figure 1.

Membrane traffic-mediated regulation of N-cadherin plays critical roles in multiple modes of neuronal migration and morphological changes.

(A) Immature neurons exhibit multiple steps of migration. (i) Radial glial cells are neural progenitors, which directly or indirectly give rise to immature neurons. Newly generated neurons extend immature neurites and exhibit multipolar morphologies. (ii) The multipolar neurons repeatedly extend and retract immature neurites, but subsequently eliminate all immature neurites, besides an axon. (iii) Almost concurrently with the immature neurite pruning, the neurons form a pia-directed thick leading process, resulting in a bipolar morphology. (iv) The bipolar-shaped neurons, called locomoting neurons, undergo long-distance migration along the radial fibers. (v) At the final phase of migration, the neurons undergo terminal translocation. (B) Reelin promotes GDP/GTP exchange reaction of Rap1, which activates α5β1-integrin, a fibronectin receptor, at the front side of the leading process in the outermost layer (layer I) of the cerebral cortex. N-cadherin is also a downstream of Rap1 and may be involved in the terminal translocation. (C) N-cadherin is essential for the attachment of the locomoting neurons to the radial fibers. N-cadherin is internalized and recycled to the forward plasma membrane to promote forward movement along the radial fibers, which is executed by the cooperative and/or sequential activation of Rab5, Rab11, Arf6, and FIP3 (see the main text). Rap1 is required for the stabilization of N-cadherin at the plasma membrane. (D) The immature neurite pruning requires N-cadherin internalization, which is regulated by Rab21 and caveolin-1. Rab21 recruits and may stabilize caveolin-1 at the plasma membrane. The internalized N-cadherin may be transported in part toward the cell front to extend the leading process. Created with Adobe Illustrator. α and β: α- and β-catenins, respectively; α5/β1: α5β1-integrin heterodimer; GTP-Rap1: an activated form of Rap1.