Directional Sorting And Transport

Which mechanisms encode that a transport complex moves in a certain direction of a polar neuron? As discussed above, cargo recognition is important to form the transport complex; however the following example shows that individual molecules, which link motor and cargo, might be directly involved in the determination of transport direction. Transport vesicles containing AMPA receptors destined for the postsynaptic specialization are transported to dendrites through interaction with the AMPA receptor-interacting protein GRIP1, which binds to the C-terminal tail of KIF5 (Figure 13.2). The KIF5-binding domain of GRIP1 consists of amino acid residues 753-987 in the GRIP1 polypeptide, a region located between the sixth and seventh PDZ domain of GRIP1. Upon overexpression of this motif, endogenous KIF5 accumulates predominantly in the somatodendritic area of the neuron. In contrast, when the kinesin light chain interacting protein JIP3 is overexpressed, KIF 5 accumulates in the somatoaxonal area6. This indicates that cargo binding or the nature of the adaptor/cargo complex steers cargoes to specific subcellular domains, such as axons and dendrites.

It is not yet clear whether this phenomenon represents a general principle or applies to individual transport complexes; however other cellular mechanisms contribute to selectively sort and transport proteins to axons and dendrites. It has been a matter of debate whether motors are smart and would be able to distinguish between axons and dendrites, since individual motors, such as KIF21B, specifically move to dendrites22. However, the fact that many motors transport cargo in both compartments rather suggests that other mechanisms mainly account for the sorting of motors. For instance the polarity of microtubules differs between axons and dendrites. This difference could contribute in achieving polarized transport to different neuronal compartments.

Given the nature of the axon initial segment, it seems likely that a structural component critically contributes to sorting of material in particular to the axon. If one considers the three-dimensional structure of a neuronal soma with an axon diameter of approximately one-tenth of that of the cell body, axonally transported material needs to be sorted from the cell body in only about 0.25% of all possible directions to enter the axon23. Therefore, to circumvent this problem, unique components, such as for instance the nature of the tracks that extend into the axon initial segment, could direct transport complexes destined for the axon. In consistence with this view, the fusion of the KIF5 motor domain to GFP, generates a fusion protein that, when expressed in hippocampal neurons, specifically accumulates at the tips of axons. This finding indicates that the motor domain alone, lacking peripheral sequences for cargo binding, has a preference for axonal delivery23. Moreover, a KIF5 mutant that binds microtubules, but is neither able to translocate nor to dissociate from the tracks, accumulates in the axon initial segment, further indicating that this motor domain has a preference for microtubules particular at this subcellular region. Consequently, the nature of the tracks will have to be considered as critical for sorting processes in a polar cell, such as for instance a pyramidal neuron with many dendrites and a single axon.

Microtubules are decorated by MAPs. Some of these proteins, such as Tau, which selectively binds to axonal microtubules, are highly phosphorylated at various residues24,25. Given the high number of MAPs expressed in neurons in combination with the many post-translational modifications used in cells, one could consider that a large variety of individual tracks exist that contribute to the sorting of individual transport complexes.

Despite the described mechanisms to regulate sorting at the level of the track, the motor or the cargo adaptor, many proteins to be transported harbor sorting signals that can be divided into axonal and dendritic targeting sequences. Signals that have been identified for neuronal transport include dileucine-based motifs, tyrosine-based motifs or palmitoylation of cysteine residues26-28. The transport to dendrites is often considered to be analogous to basolateral transport in epithelial cells, in which proteins undergo polarized sorting to apical and basolateral compartments. Consistently, a GFP-tagged transferrin receptor (TfR), which is a marker for basolateral sorting in epithelial cells, localizes selectively to neuronal dendrites and rarely enters the axon. The TfR dendritic targeting signal is located in the N-terminal tail of the polypeptide and represents a tyrosine-based sequence26. For the postsynaptic density protein 95 (PSD-95), an N-terminal palmitoylation signal is necessary for dendritic targeting to dendrites28. However, in this case the motif itself is not sufficient for the targeting process, suggesting that other sequences are involved in the targeting process of PSD-95. In contrast, for the lipid-anchored peripheral protein GAP43, a palmitoylation motif within its polypeptide sequence is indeed sufficient for axonal targeting. Interestingly, when this GAP43-derived sequence is fused to PSD-95, the resulting chimera is redirected to axons. For metabotopic glutamate receptors (mGluRs), mGluR1a is targeted to dendrites, however its alternative splice transcript mGluR1b is targeted to axons29,30. In this case, alternative splicing generates a tripeptide motif that directs the protein to the axonal compartment.

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