Polarisation of the cell surface into structurally and functionally discrete sub-domains is a characteristic feature of most eukaryotic cells. Two general mechanisms are thought to contribute to the generation and maintenance of cell-surface polarization: proteins are either selectively delivered to particular surface regions, or delivered equally to all regions and selectively retained at the appropriate cell-surface domains. The axon and dendrite are functionally distinct polarized domains of a neuron. Current evidence favours a role for selective retention in axonal polarization. Now, a study by Sampo and colleagues (Neuron 37, 611–624 (2003)) suggests that in addition to selective retention, selective delivery also has an important role in axonal polarization.

Role of the NgCAM ectodomain in polarized transport. A fluorescence image showing soluble green fluorescent protein (GFP; green, axons and dendrites) and a chimaera of the NgCAM ectodomain and the cytoplasmic domain of the unpolarized protein CD8 (red, axonal surface, but not dendrites). Figure adapted from Sampo et al. © (2003), with permission from Elsevier Science.

To gain insights into the processes that govern axonal polarization, the authors examined trafficking of Vamp2 and NgCAM, two proteins that are selectively transported to the axonal cell surface. The authors first reasoned that preferential endocytosis from the dendritic cell surface may result in the axonal distribution of proteins. Although Vamp2-containing endosomes were found in dendrites, NgCAM was not present in these endosomes in the majority of hippocampal neurons. Moreover, an endocytosis-deficient Vamp2 mutant was no longer selectively transported to the axon, but rather, had the distribution of a protein that is transported in a non-polarized fashion. In contrast, disruption of the endocytosis motif in NgCAM and another axonal protein, L1, did not prevent the axonal distribution of either protein (see Figure). These findings strongly suggest that selective retention of Vamp2 at the axonal surface maintains the axonal polarization of Vamp2.

In contrast to Vamp2, the extracellular domain (rather than the cytoplasmic domain) of NgCAM contains essential determinants for polarization. In particular, it contains five fibronectin type III-like (FnIII) repeats in the extracellular domain that are necessary for selective axonal targeting. When grafted onto a related, but unpolarized, protein such as NrCAM, these five FnIII repeats were sufficient to redistribute NrCAM to the axonal surface, suggesting that selective sorting and delivery result in the axonal distribution of NgCAM.

These studies demonstrate that polarization of proteins to the axon relies on both selective retention and selective delivery. It remains unclear exactly how Vamp2 is preferentially retained at the axonal surface and how selective sorting of NgCAM is accomplished. Future work will undoubtedly provide further insights into these and other aspects of neuronal polarization.