Regulation of axon growth and guidance by lipid rafts

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During development, the tip of axons, called the growth cone, expresses various functional molecules that regulate axon elongation and guidance. In cell membranes, proteins and lipids are not uniformly distributed but form spatially differentiated microdomains, such as lipid rafts composed predominantly of cholesterol and sphingolipids. It has been reported that the cell adhesion molecule L1, a transmembrane protein involved in axon elongation, is localized to lipid rafts and that rafts in the growth cone periphery is critical for axon elongation (J Cell Biol 159 : 1097-1108, 2002). In this project, we have conducted differential proteomic studies to search for proteins that translocate into or out of lipid rafts in response to ligand binding to L1 expressed on neurons in culture. These studies identified two proteins, munc-18 and synaptophysin, both of which are implicated in the regulation of membrane exocytosis. Therefore, we next investigated the role of membrane exocytosis in axon growth and guidance. Endocytic vesicles in growth cones were labeled with FM1-43 and their movement was monitored. We found that the growth cone turning is accompanied by selective transport of endocytic vesicles to the side facing the new direction. VAMP2-positive exocytosis-competent vesicles showed the similar pattern of movement. We also found that the transported vesicles are exocytosed at the growth cone periphery. This work has demonstrated that the growth cone turns by preferentially supplying membrane components to the side facing the new direction and suggested that lipid rafts could be involved in the regulation of membrane exocytosis.