Key Points
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In neurons, most proteins that are needed in the axon are synthesized in the cell body and selectively transported to the axon. Most dendritic proteins are also selectively transported from the cell body, but several specific mRNAs are transported into dendrites to support local protein synthesis.
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For transport of membranous organelles, macromolecular complexes and mRNAs in the axons and dendrites, microtubules serve as rails and kinesin superfamily proteins (KIFs) function as anterograde motors. Microtubules have polarity, with a plus end and a minus end.
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Forty-five KIF genes have been identified in mice and humans. All kinesins have a motor domain that shows high degrees of homology. However, regions outside the motor domains are unique, and these regions allow various cargoes to be recognized and differentially transported.
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Recently, unified family names for classification of kinesins in all phylogenies (Kinesin 1 to Kinesin 14) have been defined, but individual motor names will remain the same. The KIF5 family corresponds to conventional kinesin.
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Most kinesins move towards the plus end of microtubules, which takes them from the cell body towards the nerve terminal. The KIF2 family is unique in having both plus-end-directed motor activity and microtubule-depolymerizing activity, which is used to control axon collateral extension at the growth cone.
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Adaptor/scaffolding proteins tend to be used for the binding of kinesins to cargoes. Examples are the use of the adaptor protein 1 (AP1) adaptor complex, scaffolding proteins, including proteins of the JNK signalling pathway called JIPs and glutamate receptor-interacting protein 1 (GRIP1), and a tripartite scaffolding protein complex containing LIN10, LIN2 and LIN7 for transporting selective membrane cargoes. The molecular interactions of kinesins, adaptor/scaffolding proteins and cargoes have been elucidated in detail in these examples.
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KIF5 transports various cargoes to both axons and dendrites. Both the carboxy-terminal tail of KIF5 and the associated light chain can serve as binding sites for cargoes, and they might be differentially used for selective transport. Cargoes bound to kinesin light chain tend to be transported to axons, whereas those bound to the KIF5 tail are transported to dendrites.
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mRNAs are transported in dendrites as a large multisubunit complex of 42 proteins that binds to the tail of KIF5.
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The microtubule bundle at the initial segment, which shows characteristically strong binding to EB1 (a microtubule-associated protein), serves as a cue for KIF5 to enter axons.
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Many mechanisms might be used to achieve selective transport of various cargoes. However, a basic understanding of the transport process from the viewpoint of motors and their association with cargoes will clarify the common principles of selective transport.
Abstract
Intracellular transport is fundamental for neuronal morphogenesis, function and survival. Many proteins are selectively transported to either axons or dendrites. In addition, some specific mRNAs are transported to dendrites for local translation. Proteins of the kinesin superfamily participate in selective transport by using adaptor or scaffolding proteins to recognize and bind cargoes. The molecular components of RNA-transporting granules have been identified, and it is becoming clear how cargoes are directed to axons and dendrites by kinesin superfamily proteins. Here we discuss the molecular mechanisms of directional axonal and dendritic transport with specific emphasis on the role of motor proteins and their mechanisms of cargo recognition.
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Acknowledgements
We thank all members of the Hirokawa laboratory and Okinaka Memorial Institute for Medical Research. This work was supported by a Center of Excellence grant to N.H. from the Ministry of Education, Culture, Sports, Science and Technology.
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Glossary
- MOLECULAR MOTOR SUPERFAMILIES
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Kinesin and dynein superfamily proteins move along microtubules, and myosin superfamily proteins move along actin filaments by ATP hydrolysis.
- ANTEROGRADE AND RETROGRADE TRANSPORT
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The direction of anterograde axonal transport is from the cell body to the synapses, whereas that of retrograde axonal transport is from the synapses to the cell body.
- FAST AXONAL TRANSPORT
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Membranous organelles are transported by fast axonal transport at ∼400 mm day−1, whereas cytosolic and cytoskeletal proteins are transported by slow axonal transport at ∼0.2–2.5 mm day−1.
- CHARCOT-MARIE-TOOTH DISEASE
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(CMT). The most common inherited peripheral neuropathy, characterized by weakness and atrophy of distal muscles, depressed or absent deep-tendon reflexes and mild sensory loss. Type II is an axonopathy and type I is a myelopathy.
- APOER2
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(Apolipoprotein E receptor 2). A member of the low density lipoprotein receptor gene family, which binds APOE-containing lipoproteins. It is also a receptor for the reelin ligand on migrating neurons.
- REELIN
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The gene that is disrupted in the spontaneous mutant mouse reeler, which shows disrupted cellular organization in the brain due to aberrant migration of neurons. Reelin encodes an extracellular molecule that controls neuronal cell positioning.
- GAP43
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A growth-associated, membrane-bound phosphoprotein, expression of which is markedly elevated during neuronal development and regeneration.
- VAMP2
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VAMP (vesicle-associated membrane protein) is also called synaptobrevin. VAMPs are synaptic vesicle proteins that are required for calcium-dependent exocytosis at synaptic terminals, and are also present on the axonal surface.
- FODRIN
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A spectrin family protein that is expressed in nonerythroid cells.
- NERVE LIGATION
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When a nerve (such as the sciatic nerve) is ligated experimentally, anterogradely transported cargoes accumulate on the proximal side and retrogradely transported cargoes on the distal side of the ligated point.
- S VALUE
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Sedimentation coefficient expressed in Svedberg units, whichare defined as 10−13 sec. This unit is used to characterize a protein's sedimentation behaviour and is higher for larger (higher molecular weight) proteins.
- PUR PROTEINS
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The PUR factor was originally identified as a protein that binds to purine-rich, single-stranded DNA sequences adjacent to a region of stably bent DNA upstream of the human MYC gene.
- STAUFEN
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Staufen was originally identified as a maternal factor that is required for the anteroposterior axis in Drosophila melanogaster embryos. It is an RNA-binding protein and is responsible for the localization of mRNAs.
- RNA HELICASES
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A family of proteins that have a helicase domain, which binds and unwinds RNAs. They have been implicated in mRNA transport, splicing and translation. Putative human RNA helicases have been assigned the gene symbol DDX.
- HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEINS
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(hnrnps). A group of proteins that bind to nascent RNA polymerase II transcripts and package heterogeneous nuclear RNAs into hnRNP particles in the nucleus. They have an RNA-binding motif and also function in cytoplasmic mRNA translation and turnover.
- MULTIVESICULAR BODY
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An organelle with a multivesicular (inner vesicles within a vesicle) appearance, identified by thin-section transmission electron microscopy. It is a subset of late endosomes that might function in receptor downregulation.
- NODE CELLS
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Ciliated cells, which have monocilia that rotate and generate a leftward nodal flow of extra-embryonic fluid. They are crucial for the formation of the left–right axis in an early embryo.
- MANNOSE-6-PHOSPHATE RECEPTOR
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(M6PR). The receptor for mannose-6-phosphate, which serves as a recognition signal for the transport of newly synthesized lysosomal hydrolases from the trans-Golgi network to endosomes, and for the uptake of external ligands on the cell surface by receptor-mediated endocytosis with coated pits.
- AP1 ADAPTOR COMPLEX
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A heterotetrameric complex composed of β1, γ, μ1 and δ1 subunits that functions as an adaptor for clathrin-mediated traffic.
- LIN
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The Caenorhabditis elegans PDZ proteins, LIN-2, LIN-7 and LIN-10 were identified by the analysis of the genes lin-2, lin-7, and lin-10, which define the basolateral distribution of epithelial proteins. The mammalian homologue of LIN-10 is also called MINT1 (Munc18-interacting protein); LIN-2 is also called CASK; and LIN-7 is called VELIS (for vertebrate LIN-7 homologue) or MALS (for mammalian LIN-7 protein).
- PDZ DOMAIN
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A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins. PDZ containing proteins often contain multiple PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD-95, discs large, zona occludens 1).
- TETRATRICOPEPTIDE REPEAT MOTIF
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(TPR motif). Tandem repeats of degenerate 34 amino acids, which mediate protein–protein interactions. TPR-containing proteins are involved in biological processes such as transcriptional control, mitochondrial and peroxisomal protein transport, and neurogenesis.
- JNK SIGNALLING PATHWAY
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JNK was identified as a microtubule-associated protein kinase. It binds to the amino terminus of c-Jun and phosphoroylates c-Jun. JNK is activated by various cytokines and environmental stresses.
- FMRP
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A set of proteins derived from the alternative splicing of Fragile X mental retardation gene 1; FMRP, an RNA-binding protein, and the two highly homologous proteins FXR1P and FXR2P, are proposed to participate in mRNA transport.
- ConA
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Concanavalin A is a member of the lectin family. Lectins are proteins that bind tightly to specific sugars and are often used experimentally to bind to cell surface glycoproteins. ConA is purified from the plant Canavalia ensiformis and has specificity for α-D-mannose and α-D-glucose.
- EB1
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EB1 belongs to a family of evolutionarily conserved proteins, and binds to the plus ends of microtubules in diverse cell types. The end-binding mechanism remains unknown, but might use dynamic or structural cues found at microtubule ends.
- NgCAM
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The neuron–glia cell adhesion molecule is a member of the immunoglobulin (Ig) superfamily of neural cell adhesion molecules, which are thought to play a role in axonal pathfinding and fasciculation.
- TYROSINE-BASED AND DILEUCINE-BASED MOTIFS
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Tyrosine-based motifs (such as NPXY or YXXφ) and dileucine-based motifs (such as [DE]XXXL[LI] or DXXLL) are recognized by components of the protein coats of adaptor protein complexes.
- T1 DOMAIN
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A domain that is required for the tetramerization of the four subunits that associate to form the central pore of a potassium channel.
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Hirokawa, N., Takemura, R. Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6, 201–214 (2005). https://doi.org/10.1038/nrn1624
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DOI: https://doi.org/10.1038/nrn1624
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