NgCAM gets internalized (red) on the way to the axon (blue).

To establish and maintain their asymmetrical structure, neurons must sort different proteins to their somatodendritic and axonal membranes. Previous work has supported three different models to explain selective transport to axons: direct transport to the axon; selective fusion of vesicles with the axon; and transport to the somatodendritic membrane followed by transcytosis. A detailed analysis by Wisco et al. (page 1317) now identifies evidence that the adhesion molecule NgCAM can take two of these three paths.

Some recent evidence suggests that vesicles containing NgCAM are blocked from fusing with the somatodendritic membrane in the first place. But in a kinetic analysis, Wisco et al. show that in fact NgCAM does transiently appear on the somatodendritic membrane, but is then endocytosed and sent to the axonal membrane by a transcytotic pathway.

The NgCAM protein encodes all of the signals necessary to direct it to the transcytotic pathway. A mutant NgCAM protein lacking the transcytosis signal is instead sent directly to the axonal membrane from the trans-Golgi network, suggesting that two distinct pathways are available to NgCAM, but transcytosis normally supersedes direct targeting. The authors now hope to determine whether this circuitous route is unique to NgCAM or common to many axonal proteins. ▪