Recycling of the cell adhesion molecule L1 in axonal growth cones

The cell adhesion molecule (CAM) L1 plays crucial roles in axon growth in v itro and in the formation of major axonal tracts in vivo. It is generally t hought that CAMs link extracellular immobile ligands with retrogradely movi ng actin filaments to transmit force that pulls the growth cone forward. Ho wever, relatively little is known about the fate of CAMs that have been tra nslocated into the central (C)-domain of the growth cone. We have shown pre viously that L1 is preferentially endocytosed at the C-domain. In the prese nt study, we further analyze the subcellular distribution of endocytic orga nelles containing L1 at different time points and demonstrate that internal ized L1 is transported into the peripheral (P)-domain of growth cones advan cing via an L1-dependent mechanism. Internalized L1 is found in vesicles po sitioned along microtubules, and the centrifugal transport of these L1-cont aining vesicles is dependent on dynamic microtubules in the P-domain. Furth ermore, we show that endocytosed L1 is reinserted into the plasma membrane at the leading edge of the P-domain. Monitoring recycled L1 reveals that it moves retrogradely on the cell surface into the C-domain. In contrast, the growth cone advancing independently of L1 internalizes and recycles L1 wit hin the C-domain. For the growth cone to advance, the leading edge needs to establish strong adhesive interactions with the substrate while attachment s at the rear are released. Recycling L1 from the C-domain to the leading e dge provides an effective way to create asymmetric L1-mediated adhesion and therefore would be critical for L1-based growth cone motility.