We have discovered a novel actin/myosin-based mechanism that underlies the targeting of transmembrane proteins to the dendritic compartment or to the surface of the axon. We have shown that Myosin Va is necessary and sufficient, and actin filaments are necessary, for targeting of transmembrane proteins to the somatodendritic compartment (1). Conversely, we found that Myosin VI, is necessary and sufficient for localization of proteins to the surface of the axon (2).
Since Myosin Va moves to the plus end of actin filaments, while Myosin VI moves to the minus end, these results are consistent with a model for a vesicle filter within the axon initial segment (AIS) consisting of actin filaments (Figs. 1 and 2). Dendritic proteins are carried in vesicles that associate with both a kinesin motor and with Myosin Va (Fig. 1). The kinesin motor carries the vesicles along microtubules to the AIS where Myosin Va interacts with actin filaments causing the vesicles to stop and move back towards the cell body. In contrast when vesicles carrying dendritic proteins move along microtubules that project to the dendrites, they move unimpeded to the distal dendrites. When vesicles carrying axonal proteins move to the AIS Myosin VI interacts with actin filaments and moves towards the distal axon. When these vesicles move to the dendrites, they deposit their contents on the surface of the dendrites. As soon as the proteins appear on the dendritic plasma membrane they are immediately endocytosed as a result of the actions of Myosin VI.
To test this model we observed vesicle movement in living neurons (3). We found that vesicles carrying transmembrane proteins entered axons and dendrites with equal frequency following exit from the Golgi, regardless of the vesicle cargo. However, once in the AIS most vesicles carrying dendritic proteins halted and reversed before they could move to the distal axon. In contrast, the vast majority of vesicles carrying axonal proteins moved through the proximal axon unimpeded. Thus, vesicles carrying transmembrane proteins move as predicted by the model in Figs. 1 and 2.