Vesicular Sorting to Axons and Dendrites

Introduction

Neurons are highly polarized cells characterized by unique axonal and somatodendritic domains. Vesicular sorting of transmembrane proteins to each of these domains occurs by selective incorporation of the proteins into different populations of somatodendritic and axonal carrier vesicles in the neuronal soma. These vesicles then move to their corresponding neuronal domains along cytoskeletal tracks.

The boundary between the somatodendritic and axonal domains has been located at the axon initial segment (AIS). AIS consists of a high concentration of surface voltage-gated ion channels and cell-adhesion molecules that are anchored by a submembranous assembly of bIV-spectrin and ankyrin G (AnkG). The channels perform the main function of the AIS, namely generation of action potentials in response to somatodendritic inputs. Besides, the highly ordered structure of the AIS constitutes a barrier for the diffusional mobility of plasma membrane proteins and lipids between the axonal and somatodendritic domains.

Fig.1 Structure of the AIS and its key components. (Jones, 2016)

Controversy?

For a long time before, an unresolved controversy is how the vesicles are sorted to their corresponding neuronal domains. Previous studies concluded that the AIS is an actin-based filter that allows passage of axonal, but not somatodendritic, vesicles toward the distal axon. Recently, this notion has been challenged recently by several findings.

1. Firstly, analysis by platinum replica electron microscopy revealed that the AIS cytoplasm does not contain polarized actin arrays or a dense actin network, but only exhibits sparse actin filaments with mixed orientation.
2. Secondly, though treatment with drugs that disrupt filamentous actin abrogates the polarized distribution of some proteins, this has been shown to result from altered sorting into the corresponding transport.
3. Thirdly, live-cell imaging assays showed that, during neuronal development in culture, polarized transport of somatodendritic and axonal vesicles is established before the appearance of the AIS.

Together, these results have prompted scientists to reassess the role of AIS in sorting somatodendritic and axonal vesicles.

Fig.2 Schematic representation of vesicle sorting at the PAEZ. (Farías, 2015)

Advances

Recent studies showed that sorting of most somatodendritic and axonal carrier vesicles in hippocampal neurons occurs not at the AIS. This process occurs at a proximal pre-axonal exclusion zone (PAEZ) located in the axon hillock or at the base of axons that emanate from dendrites. Most somatodendritic vesicles budding from the Golgi complex fail to enter the axon at the PAEZ. Fusion of a kinesin light chain-binding sequence to a somatodendritic protein overcomes exclusion at the PAEZ, promoting transport of whole somatodendritic vesicles through the PAEZ and AIS, all the way to the distal axon.

Briefly, these findings support that sorting of somatodendritic and axonal vesicles at the PAEZ depends on the ability of the vesicles to acquire an appropriately directed microtubule motor.

References

1. Jones, S. L.; Svitkina, T. M. Axon initial segment cytoskeleton: architecture, development, and role in neuron polarity. Neural plasticity. 2016, 2016.
2. Farías, G. G.; et al. Sorting of dendritic and axonal vesicles at the pre-axonal exclusion zone. Cell reports. 2015, 13(6): 1221-1232.