The Role Of Endocytosis In Neuronal Migration

Disruptions in neuronal migration have been implicated in a variety of human mental disorders, including epilepsy, autism, and schizophrenia. Despite the critical role of migration during nervous system development, the basic physical and cytoskeletal mechanisms of coordinated neuronal movement have not yet been fully characterized. A migrating neuron moves with morphologically distinct steps: a single leading process extends ahead of a stationary cell soma, followed by the formation of a cytoplasmic dilation ahead of the nucleus, subsequent movement of the nucleus into the dilation, and retraction of the cell rear. The temporal and spatial regulation of adhesion is important for the proper progression of these steps. I investigated the role of endocytosis in regulating adhesion during neuronal migration. Using genetic and pharmacological methods to disrupt endocytosis either in vitro or in vivo leads to altered neuronal migration. Introducing dominant negative clathrin or dynamin into the developing cortex delays radial migration in vivo. Pharmacologically inhibiting clathrin or dynamin reduces the velocity of anterior subventricular zone (SVZa) neurons migrating in a three-dimensional matrix in vitro. Components of clathrin endocytic machinery are localized to the dilation region of a migrating neuron at points of matrix attachment. The absence of adhesion molecules at the cell rear led us to the hypothesis that endocytosis weakens adhesions in the dilation to allow the cell rear to move forward during migration. In support of this hypothesis, exposing SVZa explants to pharmacological inhibitors of either clathrin or dynamin prevents migration out of explants, and neurons that have migrated out have altered morphology and adhesion molecule distribution. Neurons exposed to a dynamin inhibitor tend to have "tails" of membrane at the rear, and these tails contain adhesion molecules. The presence of adhesion molecules at the rear of migrating neurons exposed to a dynamin inhibitor supports the idea that endocytosis plays a role in regulating adhesion disassembly. Endocytosis likely plays a critical role in general neuronal migration regardless of the specific neuronal subtype, migration mode, or substrate.