The generation and maintenance of neuronal polarity depends on the differential distribution of key proteins to the axonal or dendritic compartment. This could be achieved in at least two ways — proteins might be specifically targeted to certain projections ('selective delivery'), or they might initially be distributed more evenly through the cell and subsequently become eliminated from certain regions ('selective retention'). In a new paper in Neuron, Sampo et al. show that both of these systems operate in neurons, and that different mechanisms are employed by different proteins.

The neuronal membrane proteins vesicle-associated membrane protein 2 (Vamp2) and neuron–glia cell adhesion molecule (NgCAM) are both preferentially localized to the axon. Both proteins are transported into dendrites, but very little Vamp2 or NgCAM are detected on the dendritic membrane. Each protein contains an intracellular signal sequence that enables them to undergo endocytosis, so both could potentially be internalized after delivery to the dendritic membrane. Indeed, the behaviour of Vamp2 is consistent with such a model. Sampo et al. showed that mutation of the Vamp2 endocytosis signal abolished the polarized distribution of this protein, resulting in equal distribution between axonal and dendritic membrane domains.

By contrast, removal of the NgCAM endocytosis signal had no effect on the subcellular distribution of this protein. However, the authors found that if they removed a series of fibronectin type III-like (FnIII) repeats from the extracellular domain of NgCAM, the molecule could now be incorporated into the dendritic membrane. Furthermore, addition of these repeats to a closely related protein, NrCAM, which does not normally have a polarized distribution, caused this molecule to be directed preferentially to the axonal membrane. This indicates that the FnIII repeats are both necessary and sufficient to ensure that NgCAM is targeted specifically to the axon.

In summary, these findings provide compelling evidence that Vamp2 is eliminated from the dendritic membrane by selective retention, whereas carriers containing NgCAM are prevented from fusing with the dendritic plasma membrane. Sampo et al. propose that VAMP2 and NgCAM are transported around the cell by different carrier vesicles, but further experiments will be required to confirm this idea. The answer to this and other questions should provide us with some important new insights into the molecular and cellular mechanisms that underlie neuronal polarity.