Journal articles: 'Anterograde transport'

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Kondo, S., R. Sato-Yoshitake, Y. Noda, H. Aizawa, T. Nakata, Y. Matsuura, and N. Hirokawa. "KIF3A is a new microtubule-based anterograde motor in the nerve axon." Journal of Cell Biology 125, no. 5 (June 1, 1994): 1095–107. http://dx.doi.org/10.1083/jcb.125.5.1095.

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Neurons are highly polarized cells composed of dendrites, cell bodies, and long axons. Because of the lack of protein synthesis machinery in axons, materials required in axons and synapses have to be transported down the axons after synthesis in the cell body. Fast anterograde transport conveys different kinds of membranous organelles such as mitochondria and precursors of synaptic vesicles and axonal membranes, while organelles such as endosomes and autophagic prelysosomal organelles are conveyed retrogradely. Although kinesin and dynein have been identified as good candidates for microtubule-based anterograde and retrograde transporters, respectively, the existence of other motors for performing these complex axonal transports seems quite likely. Here we characterized a new member of the kinesin super-family, KIF3A (50-nm rod with globular head and tail), and found that it is localized in neurons, associated with membrane organelle fractions, and accumulates with anterogradely moving membrane organelles after ligation of peripheral nerves. Furthermore, native KIF3A (a complex of 80/85 KIF3A heavy chain and a 95-kD polypeptide) revealed microtubule gliding activity and baculovirus-expressed KIF3A heavy chain demonstrated microtubule plus end-directed (anterograde) motility in vitro. These findings strongly suggest that KIF3A is a new motor protein for the anterograde fast axonal transport.

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Hirata, Tetsuya, Morihisa Fujita, Shota Nakamura, Kazuyoshi Gotoh, Daisuke Motooka, Yoshiko Murakami, Yusuke Maeda, and Taroh Kinoshita. "Post-Golgi anterograde transport requires GARP-dependent endosome-to-TGN retrograde transport." Molecular Biology of the Cell 26, no. 17 (September 2015): 3071–84. http://dx.doi.org/10.1091/mbc.e14-11-1568.

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The importance of endosome-to– trans-Golgi network (TGN) retrograde transport in the anterograde transport of proteins is unclear. In this study, genome-wide screening of the factors necessary for efficient anterograde protein transport in human haploid cells identified subunits of the Golgi-associated retrograde protein (GARP) complex, a tethering factor involved in endosome-to-TGN transport. Knockout (KO) of each of the four GARP subunits, VPS51–VPS54, in HEK293 cells caused severely defective anterograde transport of both glycosylphosphatidylinositol (GPI)-anchored and transmembrane proteins from the TGN. Overexpression of VAMP4, v-SNARE, in VPS54-KO cells partially restored not only endosome-to-TGN retrograde transport, but also anterograde transport of both GPI-anchored and transmembrane proteins. Further screening for genes whose overexpression normalized the VPS54-KO phenotype identified TMEM87A, encoding an uncharacterized Golgi-resident membrane protein. Overexpression of TMEM87A or its close homologue TMEM87B in VPS54-KO cells partially restored endosome-to-TGN retrograde transport and anterograde transport. Therefore GARP- and VAMP4-dependent endosome-to-TGN retrograde transport is required for recycling of molecules critical for efficient post-Golgi anterograde transport of cell-surface integral membrane proteins. In addition, TMEM87A and TMEM87B are involved in endosome-to-TGN retrograde transport.

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Lim, Angeline, Andreas Rechtsteiner, and William M. Saxton. "Two kinesins drive anterograde neuropeptide transport." Molecular Biology of the Cell 28, no. 24 (November 15, 2017): 3542–53. http://dx.doi.org/10.1091/mbc.e16-12-0820.

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Motor-dependent anterograde transport, a process that moves cytoplasmic components from sites of biosynthesis to sites of use within cells, is crucial in neurons with long axons. Evidence has emerged that multiple anterograde kinesins can contribute to some transport processes. To test the multi-kinesin possibility for a single vesicle type, we studied the functional relationships of axonal kinesins to dense core vesicles (DCVs) that were filled with a GFP-tagged neuropeptide in the Drosophila nervous system. Past work showed that Unc-104 (a kinesin-3) is a key anterograde DCV motor. Here we show that anterograde DCV transport requires the well-known mitochondrial motor Khc (kinesin-1). Our results indicate that this influence is direct. Khc mutations had specific effects on anterograde run parameters, neuron-specific inhibition of mitochondrial transport by Milton RNA interference had no influence on anterograde DCV runs, and detailed colocalization analysis by superresolution microscopy revealed that Unc-104 and Khc coassociate with individual DCVs. DCV distribution analysis in peptidergic neurons suggest the two kinesins have compartment specific influences. We suggest a mechanism in which Unc-104 is particularly important for moving DCVs from cell bodies into axons, and then Unc-104 and kinesin-1 function together to support fast, highly processive runs toward axon terminals.

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Yezid, Hocine, Christian T. Lay, Katrin Pannhorst, and Shafiqul I. Chowdhury. "Two Separate Tyrosine-Based YXXL/Φ Motifs within the Glycoprotein E Cytoplasmic Tail of Bovine Herpesvirus 1 Contribute in Virus Anterograde Neuronal Transport." Viruses 12, no. 9 (September 14, 2020): 1025. http://dx.doi.org/10.3390/v12091025.

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Bovine herpesvirus 1 (BHV-1) causes respiratory infection and abortion in cattle. Following a primary infection, BHV-1 establishes lifelong latency in the trigeminal ganglia (TG). Periodic reactivation of the latent virus in TG neurons results in anterograde virus transport to nerve endings in the nasal mucosa and nasal virus shedding. The BHV-1 glycoprotein E cytoplasmic tail (gE-CT) is necessary for virus cell-to-cell spread in epithelial cells and neuronal anterograde transport. Recently, we identified two tyrosine residues, Y467 and Y563, within the tyrosine-based motifs 467YTSL470 and 563YTVV566, which, together, account for the gE CT-mediated efficient cell-to-cell spread of BHV-1 in epithelial cells. Here, we determined that in primary neuron cultures in vitro, the individual alanine exchange Y467A or Y563A mutants had significantly diminished anterograde axonal spread. Remarkably, the double-alanine-exchanged Y467A/Y563A mutant virus was not transported anterogradely. Following intranasal infection of rabbits, both wild-type (wt) and the Y467A/Y563A mutant viruses established latency in the TG. Upon dexamethasone-induced reactivation, both wt and the mutant viruses reactivated and replicated equally efficiently in the TG. However, upon reactivation, only the wt, not the mutant, was isolated from nasal swabs. Therefore, the gE-CT tyrosine residues Y467 and Y563 together are required for gE CT-mediated anterograde neuronal transport.

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Altar, C. Anthony, and Peter S. DiStefano. "Neurotrophin trafficking by anterograde transport." Trends in Neurosciences 21, no. 10 (October 1998): 433–37. http://dx.doi.org/10.1016/s0166-2236(98)01273-9.

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Barkus, Rosemarie V., Olga Klyachko, Dai Horiuchi, Barry J. Dickson, and William M. Saxton. "Identification of an Axonal Kinesin-3 Motor for Fast Anterograde Vesicle Transport that Facilitates Retrograde Transport of Neuropeptides." Molecular Biology of the Cell 19, no. 1 (January 2008): 274–83. http://dx.doi.org/10.1091/mbc.e07-03-0261.

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A screen for genes required in Drosophila eye development identified an UNC-104/Kif1 related kinesin-3 microtubule motor. Analysis of mutants suggested that Drosophila Unc-104 has neuronal functions that are distinct from those of the classic anterograde axonal motor, kinesin-1. In particular, unc-104 mutations did not cause the distal paralysis and focal axonal swellings characteristic of kinesin-1 (Khc) mutations. However, like Khc mutations, unc-104 mutations caused motoneuron terminal atrophy. The distributions and transport behaviors of green fluorescent protein-tagged organelles in motor axons indicate that Unc-104 is a major contributor to the anterograde fast transport of neuropeptide-filled vesicles, that it also contributes to anterograde transport of synaptotagmin-bearing vesicles, and that it contributes little or nothing to anterograde transport of mitochondria, which are transported primarily by Khc. Remarkably, unc-104 mutations inhibited retrograde runs by neurosecretory vesicles but not by the other two organelles. This suggests that Unc-104, a member of an anterograde kinesin subfamily, contributes to an organelle-specific dynein-driven retrograde transport mechanism.

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Uchida, Atsuko, Nael H. Alami, and Anthony Brown. "Tight Functional Coupling of Kinesin-1A and Dynein Motors in the Bidirectional Transport of Neurofilaments." Molecular Biology of the Cell 20, no. 23 (December 2009): 4997–5006. http://dx.doi.org/10.1091/mbc.e09-04-0304.

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We have tested the hypothesis that kinesin-1A (formerly KIF5A) is an anterograde motor for axonal neurofilaments. In cultured sympathetic neurons from kinesin-1A knockout mice, we observed a 75% reduction in the frequency of both anterograde and retrograde neurofilament movement. This transport defect could be rescued by kinesin-1A, and with successively decreasing efficacy by kinesin-1B and kinesin-1C. In wild-type neurons, headless mutants of kinesin-1A and kinesin-1C inhibited both anterograde and retrograde movement in a dominant-negative manner. Because dynein is thought to be the retrograde motor for axonal neurofilaments, we investigated the effect of dynein inhibition on anterograde and retrograde neurofilament transport. Disruption of dynein function by using RNA interference, dominant-negative approaches, or a function-blocking antibody also inhibited both anterograde and retrograde neurofilament movement. These data suggest that kinesin-1A is the principal but not exclusive anterograde motor for neurofilaments in these neurons, that there may be some functional redundancy among the kinesin-1 isoforms with respect to neurofilament transport, and that the activities of the anterograde and retrograde neurofilament motors are tightly coordinated.

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Carmichael, Stephen W., and Jeffery L. Salisbury. "Watching Rafts Move Within Cells: A Fluorescence Microscope-Based Transport Assay." Microscopy Today 8, no. 1 (January 2000): 3–7. http://dx.doi.org/10.1017/s1551929500057059.

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Imagine a raft in a canal between point A and point B. On that raft is a visible (fluorescent) cargo. Also, attached to that raft is a motor that will propel the raft only from A to B (anterograde transport). When the raft gets to point B, another motor is attached that can propel the raft, and its cargo, and the anterograde motor, back to point A (retrograde transport). Within a cell, the canals are microtubLiles, and a lot is known about anterograde and retrograde transport in some systems, but these phenomena have not been directly observed in a living, intact animal. Until now, that is. In a pair of very interesting papers, the laboratory of Jonathan Scholey has shown us convincing micrographs of anterograde and retrograde transport in an important animal model.

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9

Snyder, R. E., and R. S. Smith. "Rapid axonal transport in Xenopus nerve in divalent cation free media." Canadian Journal of Physiology and Pharmacology 63, no. 10 (October 1, 1985): 1279–90. http://dx.doi.org/10.1139/y85-212.

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An investigation was made of the effects of bathing media low in divalent cations on rapid axonal transport in the sciatic nerve of the amphibian Xenopus laevis. The anterograde transport of a pulse of [35S]methionine proteins was observed using a multiple proportional counter as the detector. Organelles undergoing anterograde and retrograde transport were detected by light microscopy. The structure of nerve fibres was examined by light and electron microscopy. There was no significant difference in the anterograde transport of proteins in nerves bathed in normal medium (NM) containing millimolar Ca2+ and Mg2+ and in those bathed in calcium-free medium (CaFM) containing Mg2+. The anterograde transport of labelled proteins continued at a normal velocity in nerves bathed in divalent cation free medium (DCFM) for at least 14 h. DCFM did cause some alterations in protein transport: the ratio of the plateau (following pulse passage) to the peak radioactivity was increased, the pulse amplitude decreased more rapidly, and the label continued to arrive at the distal end of the nerve for >16 h. Anterograde and retrograde organelle transport continued normally for periods of [Formula: see text] in fibres bathed in DCFM. All myelinated fibres became distorted within 4 h in DCFM. Similar distortion was rare in fibres bathed in CaFM. The results indicate that axonal transport in Xenopus is largely independent of lowered concentrations of divalent cations in the bathing medium. Those alterations in axonal transport that were produced by DCFM may have been secondary to morphological changes in the nerve fibres.

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Cavolo, Samantha L., Chaoming Zhou, Stephanie A. Ketcham, Matthew M. Suzuki, Kresimir Ukalovic, Michael A. Silverman, Trina A. Schroer, and Edwin S. Levitan. "Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles." Molecular Biology of the Cell 26, no. 14 (July 5, 2015): 2664–72. http://dx.doi.org/10.1091/mbc.e14-11-1564.

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Axonal transport is critical for maintaining synaptic transmission. Of interest, anterograde and retrograde axonal transport appear to be interdependent, as perturbing one directional motor often impairs movement in the opposite direction. Here live imaging of Drosophila and hippocampal neuron dense-core vesicles (DCVs) containing a neuropeptide or brain-derived neurotrophic factor shows that the F-actin depolymerizing macrolide toxin mycalolide B (MB) rapidly and selectively abolishes retrograde, but not anterograde, transport in the axon and the nerve terminal. Latrunculin A does not mimic MB, demonstrating that F-actin depolymerization is not responsible for unidirectional transport inhibition. Given that dynactin initiates retrograde transport and that amino acid sequences implicated in macrolide toxin binding are found in the dynactin component actin-related protein 1, we examined dynactin integrity. Remarkably, cell extract and purified protein experiments show that MB induces disassembly of the dynactin complex. Thus imaging selective retrograde transport inhibition led to the discovery of a small-molecule dynactin disruptor. The rapid unidirectional inhibition by MB suggests that dynactin is absolutely required for retrograde DCV transport but does not directly facilitate ongoing anterograde DCV transport in the axon or nerve terminal. More generally, MB's effects bolster the conclusion that anterograde and retrograde axonal transport are not necessarily interdependent.

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Signor, Dawn, Karen P. Wedaman, Jose T. Orozco, Noelle D. Dwyer, Cornelia I. Bargmann, Lesilee S. Rose, and Jonathan M. Scholey. "Role of a Class Dhc1b Dynein in Retrograde Transport of Ift Motors and Ift Raft Particles along Cilia, but Not Dendrites, in Chemosensory Neurons of Living Caenorhabditis elegans." Journal of Cell Biology 147, no. 3 (November 1, 1999): 519–30. http://dx.doi.org/10.1083/jcb.147.3.519.

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The heterotrimeric motor protein, kinesin-II, and its presumptive cargo, can be observed moving anterogradely at 0.7 μm/s by intraflagellar transport (IFT) within sensory cilia of chemosensory neurons of living Caenorhabditis elegans, using a fluorescence microscope–based transport assay (Orozco, J.T., K.P. Wedaman, D. Signor, H. Brown, L. Rose, and J.M. Scholey. 1999. Nature. 398:674). Here, we report that kinesin-II, and two of its presumptive cargo molecules, OSM-1 and OSM-6, all move at ∼1.1 μm/s in the retrograde direction along cilia and dendrites, which is consistent with the hypothesis that these proteins are retrieved from the distal endings of the cilia by a retrograde transport pathway that moves them along cilia and then dendrites, back to the neuronal cell body. To test the hypothesis that the minus end–directed microtubule motor protein, cytoplasmic dynein, drives this retrograde transport pathway, we visualized movement of kinesin-II and its cargo along dendrites and cilia in a che-3 cytoplasmic dynein mutant background, and observed an inhibition of retrograde transport in cilia but not in dendrites. In contrast, anterograde IFT proceeds normally in che-3 mutants. Thus, we propose that the class DHC1b cytoplasmic dynein, CHE-3, is specifically responsible for the retrograde transport of the anterograde motor, kinesin-II, and its cargo within sensory cilia, but not within dendrites.

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Nakamura, Nobuhiro, Soh Yamazaki, Ken Sato, Akihiko Nakano, Masao Sakaguchi, and Katsuyoshi Mihara. "Identification of Potential Regulatory Elements for the Transport of Emp24p." Molecular Biology of the Cell 9, no. 12 (December 1998): 3493–503. http://dx.doi.org/10.1091/mbc.9.12.3493.

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To examine the possibility of active recycling of Emp24p between the endoplasmic reticulum (ER) and the Golgi, we sought to identify transport signal(s) in the carboxyl-terminal region of Emp24p. Reporter molecules were constructed by replacing parts of a control invertase-Wbp1p chimera with those of Emp24p, and their transport rates were assessed. The transport of the reporter was found to be accelerated by the presence of the cytoplasmic domain of Emp24p. Mutational analyses revealed that the two carboxyl-terminal residues, leucine and valine (LV), were necessary and sufficient to accelerate the transport. The acceleration was sequence specific, and the terminal valine appeared to be more important. The LV residues accelerated not only the overall transport to the vacuole but also the ER tocis-Golgi transport, suggesting its function in the ER export. Hence the LV residues are a novel anterograde transport signal. The double-phenylalanine residues did not affect the transport by itself but attenuated the effect of the anterograde transport signal. On the other hand, the transmembrane domain significantly slowed down the ER to cis-Golgi transport and effectively counteracted the anterograde transport signal at this step. It may also take part in the retrieval of the protein, because the overall transport to the vacuole was more evidently slowed down. Consistently, the mutation of a conserved glutamine residue in the transmembrane domain further slowed down the transport in a step after arriving at thecis-Golgi. Taken together, the existence of the anterograde transport signal and the elements that regulate its function support the active recycling of Emp24p.

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Chang, H. T. "Anterograde transport of lucifer yellow-dextran conjugate." Brain Research Bulletin 26, no. 5 (May 1991): 813–16. http://dx.doi.org/10.1016/0361-9230(91)90180-r.

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Martínez-Menárguez, José A., Rytis Prekeris, Viola M. J. Oorschot, Richard Scheller, Jan W. Slot, Hans J. Geuze, and Judith Klumperman. "Peri-Golgi vesicles contain retrograde but not anterograde proteins consistent with the cisternal progression model of intra-Golgi transport." Journal of Cell Biology 155, no. 7 (December 17, 2001): 1213–24. http://dx.doi.org/10.1083/jcb.200108029.

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A cisternal progression mode of intra-Golgi transport requires that Golgi resident proteins recycle by peri-Golgi vesicles, whereas the alternative model of vesicular transport predicts anterograde cargo proteins to be present in such vesicles. We have used quantitative immuno-EM on NRK cells to distinguish peri-Golgi vesicles from other vesicles in the Golgi region. We found significant levels of the Golgi resident enzyme mannosidase II and the transport machinery proteins giantin, KDEL-receptor, and rBet1 in coatomer protein I–coated cisternal rims and peri-Golgi vesicles. By contrast, when cells expressed vesicular stomatitis virus protein G this anterograde marker was largely absent from the peri-Golgi vesicles. These data suggest a role of peri-Golgi vesicles in recycling of Golgi residents, rather than an important role in anterograde transport.

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Saez, Juan, Stephanie Dogniaux, Massiullah Shafaq-Zadah, Ludger Johannes, Claire Hivroz, and Andrés Zucchetti. "Retrograde and Anterograde Transport of Lat-Vesicles during the Immunological Synapse Formation: Defining the Finely-Tuned Mechanism." Cells 10, no. 2 (February 9, 2021): 359. http://dx.doi.org/10.3390/cells10020359.

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LAT is an important player of the signaling cascade induced by TCR activation. This adapter molecule is present at the plasma membrane of T lymphocytes and more abundantly in intracellular compartments. Upon T cell activation the intracellular pool of LAT is recruited to the immune synapse (IS). We previously described two pathways controlling LAT trafficking: retrograde transport from endosomes to the TGN, and anterograde traffic from the Golgi to the IS. We address the specific role of four proteins, the GTPase Rab6, the t-SNARE syntaxin-16, the v-SNARE VAMP7 and the golgin GMAP210, in each pathway. Using different methods (endocytosis and Golgi trap assays, confocal and TIRF microscopy, TCR-signalosome pull down) we show that syntaxin-16 is regulating the retrograde transport of LAT whereas VAMP7 is regulating the anterograde transport. Moreover, GMAP210 and Rab6, known to contribute to both pathways, are in our cellular context, specifically and respectively, involved in anterograde and retrograde transport of LAT. Altogether, our data describe how retrograde and anterograde pathways coordinate LAT enrichment at the IS and point to the Golgi as a central hub for the polarized recruitment of LAT to the IS. The role that this finely-tuned transport of signaling molecules plays in T-cell activation is discussed.

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Daniel, Gina R., Patricia J. Sollars, Gary E. Pickard, and Gregory A. Smith. "Pseudorabies Virus Fast Axonal Transport Occurs by a pUS9-Independent Mechanism." Journal of Virology 89, no. 15 (May 20, 2015): 8088–91. http://dx.doi.org/10.1128/jvi.00771-15.

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Reactivation from latency results in transmission of neurotropic herpesviruses from the nervous system to body surfaces, referred to as anterograde axonal trafficking. The virus-encoded protein pUS9 promotes axonal dissemination by sorting virus particles into axons, but whether it is also an effector of fast axonal transport within axons is unknown. To determine the role of pUS9 in anterograde trafficking, we analyzed the axonal transport of pseudorabies virus in the presence and absence of pUS9.

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Martin, MaryAnn, Stanley J. Iyadurai, Andrew Gassman, Joseph G. Gindhart, Thomas S. Hays, and William M. Saxton. "Cytoplasmic Dynein, the Dynactin Complex, and Kinesin Are Interdependent and Essential for Fast Axonal Transport." Molecular Biology of the Cell 10, no. 11 (November 1999): 3717–28. http://dx.doi.org/10.1091/mbc.10.11.3717.

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In axons, organelles move away from (anterograde) and toward (retrograde) the cell body along microtubules. Previous studies have provided compelling evidence that conventional kinesin is a major motor for anterograde fast axonal transport. It is reasonable to expect that cytoplasmic dynein is a fast retrograde motor, but relatively few tests of dynein function have been reported with neurons of intact organisms. In extruded axoplasm, antibody disruption of kinesin or the dynactin complex (a dynein activator) inhibits both retrograde and anterograde transport. We have tested the functions of the cytoplasmic dynein heavy chain (cDhc64C) and the p150Glued(Glued) component of the dynactin complex with the use of genetic techniques in Drosophila.cDhc64C and Glued mutations disrupt fast organelle transport in both directions. The mutant phenotypes, larval posterior paralysis and axonal swellings filled with retrograde and anterograde cargoes, were similar to those caused by kinesin mutations. Why do specific disruptions of unidirectional motor systems cause bidirectional defects? Direct protein interactions of kinesin with dynein heavy chain and p150Glued were not detected. However, strong dominant genetic interactions between kinesin, dynein, and dynactin complex mutations in axonal transport were observed. The genetic interactions between kinesin and either Glued orcDhc64C mutations were stronger than those betweenGlued and cDhc64C mutations themselves. The shared bidirectional disruption phenotypes and the dominant genetic interactions demonstrate that cytoplasmic dynein, the dynactin complex, and conventional kinesin are interdependent in fast axonal transport.

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Chiba, Kyoko, Masahiko Araseki, Keisuke Nozawa, Keiko Furukori, Yoichi Araki, Takahide Matsushima, Tadashi Nakaya, et al. "Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport." Molecular Biology of the Cell 25, no. 22 (November 5, 2014): 3569–80. http://dx.doi.org/10.1091/mbc.e14-06-1111.

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Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity (∼2.7 μm/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b, that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11–amino acid C-terminal (C11) region with the tetratricopeptide repeat of KLC1. High frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr-668, a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons are mediated by novel roles of JIP1b.

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Herbert, Amy L., Meng-meng Fu, Catherine M. Drerup, Ryan S. Gray, Breanne L. Harty, Sarah D. Ackerman, Thomas O’Reilly-Pol, et al. "Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo." Proceedings of the National Academy of Sciences 114, no. 43 (October 12, 2017): E9153—E9162. http://dx.doi.org/10.1073/pnas.1711088114.

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Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbp transport is regulated. From a forward genetic screen for myelination defects in zebrafish, we identified a mutation in actr10, which encodes the Arp11 subunit of dynactin, a critical activator of the retrograde motor dynein. Both the actr10 mutation and pharmacological dynein inhibition in zebrafish result in failure to properly distribute mbp mRNA in oligodendrocytes, indicating a paradoxical role for the retrograde dynein/dynactin complex in anterograde mbp mRNA transport. To address the molecular mechanism underlying this observation, we biochemically isolated reporter-tagged Mbp mRNA granules from primary cultured mammalian oligodendrocytes to show that they indeed associate with the retrograde motor complex. Next, we used live-cell imaging to show that acute pharmacological dynein inhibition quickly arrests Mbp mRNA transport in both directions. Chronic pharmacological dynein inhibition also abrogates Mbp mRNA distribution and dramatically decreases MBP protein levels. Thus, these cell culture and whole animal studies demonstrate a role for the retrograde dynein/dynactin motor complex in anterograde mbp mRNA transport and myelination in vivo.

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Orci, Lelio, Mylène Amherdt, Mariella Ravazzola, Alain Perrelet, and James E. Rothman. "Exclusion of Golgi Residents from Transport Vesicles Budding from Golgi Cisternae in Intact Cells." Journal of Cell Biology 150, no. 6 (September 18, 2000): 1263–70. http://dx.doi.org/10.1083/jcb.150.6.1263.

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A central feature of cisternal progression/maturation models for anterograde transport across the Golgi stack is the requirement that the entire population of steady-state residents of this organelle be continuously transported backward to earlier cisternae to avoid loss of these residents as the membrane of the oldest (trans-most) cisterna departs the stack. For this to occur, resident proteins must be packaged into retrograde-directed transport vesicles, and to occur at the rate of anterograde transport, resident proteins must be present in vesicles at a higher concentration than in cisternal membranes. We have tested this prediction by localizing two steady-state residents of medial Golgi cisternae (mannosidase II and N-acetylglucosaminyl transferase I) at the electron microscopic level in intact cells. In both cases, these abundant cisternal constituents were strongly excluded from buds and vesicles. This result suggests that cisternal progression takes place substantially more slowly than most protein transport and therefore is unlikely to be the predominant mechanism of anterograde movement.

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Jiménez-Mateos, Eva-María, Christian González-Billault, Hana N. Dawson, Michael P. Vitek, and Jesús Avila. "Role of MAP1B in axonal retrograde transport of mitochondria." Biochemical Journal 397, no. 1 (June 14, 2006): 53–59. http://dx.doi.org/10.1042/bj20060205.

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The MAPs (microtubule-associated proteins) MAP1B and tau are well known for binding to microtubules and stabilizing these structures. An additional role for MAPs has emerged recently where they appear to participate in the regulation of transport of cargos on the microtubules found in axons. In this role, tau has been associated with the regulation of anterograde axonal transport. We now report that MAP1B is associated with the regulation of retrograde axonal transport of mitochondria. This finding potentially provides precise control of axonal transport by MAPs at several levels: controlling the anterograde or retrograde direction of transport depending on the type of MAP involved, controlling the speed of transport and controlling the stability of the microtubule tracks upon which transport occurs.

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Caleo, Matteo, and Maria Cristina Cenni. "Anterograde Transport of Neurotrophic Factors: Possible Therapeutic Implications." Molecular Neurobiology 29, no. 2 (2004): 179–96. http://dx.doi.org/10.1385/mn:29:2:179.

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Sickles, Dale W. "Toxic neurofilamentous axonopathies and fast anterograde axonal transport." Toxicology and Applied Pharmacology 108, no. 3 (May 1991): 390–96. http://dx.doi.org/10.1016/0041-008x(91)90085-s.

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DuRaine, Grayson, and David C. Johnson. "Anterograde transport of α-herpesviruses in neuronal axons." Virology 559 (July 2021): 65–73. http://dx.doi.org/10.1016/j.virol.2021.02.011.

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Holland, David J., Monica Miranda-Saksena, Ross A. Boadle, Patricia Armati, and Anthony L. Cunningham. "Anterograde Transport of Herpes Simplex Virus Proteins in Axons of Peripheral Human Fetal Neurons: an Immunoelectron Microscopy Study." Journal of Virology 73, no. 10 (October 1, 1999): 8503–11. http://dx.doi.org/10.1128/jvi.73.10.8503-8511.1999.

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ABSTRACT Herpes simplex virus (HSV) reactivates from latency in the neurons of dorsal root ganglia (DRG) and is subsequently transported anterogradely along the axon to be shed at the skin or mucosa. Although we have previously shown that only unenveloped nucleocapsids are present in axons during anterograde transport, the mode of transport of tegument proteins and glycoproteins is not known. We used a two-chamber culture model with human fetal DRG cultivated in an inner chamber, allowing axons to grow out and penetrate an agarose barrier and interact with autologous epidermal cells in the outer chamber. After HSV infection of the DRG, anterograde transport of viral components could be examined in the axons in the outer chamber at different time points by electron and immunoelectron microscopy (IEM). In the axons, unenveloped nucleocapsids or focal collections of gold immunolabel for nucleocapsid (VP5) and/or tegument (VP16) were detected. VP5 and VP16 usually colocalized in both scanning and transmission IEM. In contrast, immunolabel for glycoproteins gB, gC, and gD was diffusely distributed in axons and was rarely associated with VP5 or VP16. In longitudinal sections of axons, immunolabel for glycoprotein was arrayed along the membranes of axonal vesicles. These findings provide evidence that in DRG axons, virus nucleocapsids coated with tegument proteins are transported separately from glycoproteins and suggest that final assembly of enveloped virus occurs at the axon terminus.

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Yi, Peng, Li Li Chew, Ziwang Zhang, Hao Ren, Feiya Wang, Xiaoxia Cong, Liling Zheng, et al. "KIF5B transports BNIP-2 to regulate p38 mitogen-activated protein kinase activation and myoblast differentiation." Molecular Biology of the Cell 26, no. 1 (January 2015): 29–42. http://dx.doi.org/10.1091/mbc.e14-03-0797.

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The Cdo-p38MAPK (p38 mitogen-activated protein kinase) signaling pathway plays important roles in regulating skeletal myogenesis. During myogenic differentiation, the cell surface receptor Cdo bridges scaffold proteins BNIP-2 and JLP and activates p38MAPK, but the spatial-temporal regulation of this process is largely unknown. We here report that KIF5B, the heavy chain of kinesin-1 motor, is a novel interacting partner of BNIP-2. Coimmunoprecipitation and far-Western study revealed that BNIP-2 directly interacted with the motor and tail domains of KIF5B via its BCH domain. By using a range of organelle markers and live microscopy, we determined the endosomal localization of BNIP-2 and revealed the microtubule-dependent anterograde transport of BNIP-2 in C2C12 cells. The anterograde transport of BNIP-2 was disrupted by a dominant-negative mutant of KIF5B. In addition, knockdown of KIF5B causes aberrant aggregation of BNIP-2, confirming that KIF5B is critical for the anterograde transport of BNIP-2 in cells. Gain- and loss-of-function experiments further showed that KIF5B modulates p38MAPK activity and in turn promotes myogenic differentiation. Of importance, the KIF5B-dependent anterograde transport of BNIP-2 is critical for its promyogenic effects. Our data reveal a novel role of KIF5B in the spatial regulation of Cdo–BNIP-2–p38MAPK signaling and disclose a previously unappreciated linkage between the intracellular transporting system and myogenesis regulation.

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Shanda, Sara K., and Duncan W. Wilson. "UL36p Is Required for Efficient Transport of Membrane-Associated Herpes Simplex Virus Type 1 along Microtubules." Journal of Virology 82, no. 15 (May 21, 2008): 7388–94. http://dx.doi.org/10.1128/jvi.00225-08.

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ABSTRACT Microtubule-mediated anterograde transport is essential for the transport of herpes simplex virus type 1 (HSV-1) along axons, yet little is known regarding the mechanism and the machinery required for this process. Previously, we were able to reconstitute anterograde transport of HSV-1 on microtubules in an in vitro microchamber assay. Here we report that the large tegument protein UL36p is essential for this trafficking. Using a fluorescently labeled UL36 null HSV-1 strain, KΔUL36GFP, we found that it is possible to isolate a membrane-associated population of this virus. Although these viral particles contained normal amounts of tegument proteins VP16, vhs, and VP22, they displayed a 3-log decrease in infectivity and showed a different morphology compared to UL36p-containing virions. Membrane-associated KΔUL36GFP also displayed a slightly decreased binding to microtubules in our microchamber assay and a two-thirds decrease in the frequency of motility. This decrease in binding and motility was restored when UL36p was supplied in trans by a complementing cell line. These findings suggest that UL36p is necessary for HSV-1 anterograde transport.

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Blum, R., D. J. Stephens, and I. Schulz. "Lumenal targeted GFP, used as a marker of soluble cargo, visualises rapid ERGIC to Golgi traffic by a tubulo-vesicular network." Journal of Cell Science 113, no. 18 (September 15, 2000): 3151–59. http://dx.doi.org/10.1242/jcs.113.18.3151.

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The mechanism by which soluble proteins without sorting motifs are transported to the cell surface is not clear. Here we show that soluble green fluorescent protein (GFP) targeted to the lumen of the endoplasmic reticulum but lacking any known retrieval, retention or targeting motifs, was accumulated in the lumen of the ERGIC if cells were kept at reduced temperature. Upon activation of anterograde transport by rewarming of cells, lumenal GFP stained a microtubule-dependent, pre-Golgi tubulo-vesicular network that served as transport structure between peripheral ERGIC-elements and the perinuclear Golgi complex. Individual examples of these tubular elements up to 20 microm in length were observed. Time lapse imaging indicated rapid anterograde flow of soluble lumenal GFP through this network. Transport tubules, stained by lumenal GFP, segregated rapidly from COPI-positive membranes after transport activation. A transmembrane cargo marker, the temperature sensitive glycoprotein of the vesicular stomatitis virus, ts-045 G, is also not present in tubules which contained the soluble cargo marker lum-GFP. These results suggest a role for pre-Golgi vesicular tubular membranes in long distance anterograde transport of soluble cargo. http://www.biologists.com/JCS/movies/jcs1334.html

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McGraw, Helen M., Sita Awasthi, Jason A. Wojcechowskyj, and Harvey M. Friedman. "Anterograde Spread of Herpes Simplex Virus Type 1 Requires Glycoprotein E and Glycoprotein I but Not Us9." Journal of Virology 83, no. 17 (July 1, 2009): 8315–26. http://dx.doi.org/10.1128/jvi.00633-09.

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ABSTRACT Anterograde neuronal spread (i.e., spread from the neuron cell body toward the axon terminus) is a critical component of the alphaherpesvirus life cycle. Three viral proteins, gE, gI, and Us9, have been implicated in alphaherpesvirus anterograde spread in several animal models and neuron culture systems. We sought to better define the roles of gE, gI, and Us9 in herpes simplex virus type 1 (HSV-1) anterograde spread using a compartmentalized primary neuron culture system. We found that no anterograde spread occurred in the absence of gE or gI, indicating that these proteins are essential for HSV-1 anterograde spread. However, we did detect anterograde spread in the absence of Us9 using two independent Us9-deleted viruses. We confirmed the Us9 finding in different murine models of neuronal spread. We examined viral transport into the optic nerve and spread to the brain after retinal infection; the production of zosteriform disease after flank inoculation; and viral spread to the spinal cord after flank inoculation. In all models, anterograde spread occurred in the absence of Us9, although in some cases at reduced levels. This finding contrasts with gE- and gI-deleted viruses, which displayed no anterograde spread in any animal model. Thus, gE and gI are essential for HSV-1 anterograde spread, while Us9 is dispensable.

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He, Yan, Franto Francis, Kenneth A. Myers, Wenqian Yu, Mark M. Black, and Peter W. Baas. "Role of cytoplasmic dynein in the axonal transport of microtubules and neurofilaments." Journal of Cell Biology 168, no. 5 (February 22, 2005): 697–703. http://dx.doi.org/10.1083/jcb.200407191.

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Recent studies have shown that the transport of microtubules (MTs) and neurofilaments (NFs) within the axon is rapid, infrequent, asynchronous, and bidirectional. Here, we used RNA interference to investigate the role of cytoplasmic dynein in powering these transport events. To reveal transport of MTs and NFs, we expressed EGFP-tagged tubulin or NF proteins in cultured rat sympathetic neurons and performed live-cell imaging of the fluorescent cytoskeletal elements in photobleached regions of the axon. The occurrence of anterograde MT and retrograde NF movements was significantly diminished in neurons that had been depleted of dynein heavy chain, whereas the occurrence of retrograde MT and anterograde NF movements was unaffected. These results support a cargo model for NF transport and a sliding filament model for MT transport.

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Cevik, Sebiha, Yuji Hori, Oktay I. Kaplan, Katarzyna Kida, Tiina Toivenon, Christian Foley-Fisher, David Cottell, Toshiaki Katada, Kenji Kontani, and Oliver E. Blacque. "Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans." Journal of Cell Biology 188, no. 6 (March 15, 2010): 953–69. http://dx.doi.org/10.1083/jcb.200908133.

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The small ciliary G protein Arl13b is required for cilium biogenesis and sonic hedgehog signaling and is mutated in patients with Joubert syndrome (JS). In this study, using Caenorhabditis elegans and mammalian cell culture systems, we investigated the poorly understood ciliary and molecular basis of Arl13b function. First, we show that Arl13b/ARL-13 localization is frequently restricted to a proximal ciliary compartment, where it associates with ciliary membranes via palmitoylation modification motifs. Next, we find that loss-of-function C. elegans arl-13 mutants possess defects in cilium morphology and ultrastructure, as well as defects in ciliary protein localization and transport; ciliary transmembrane proteins abnormally accumulate, PKD-2 ciliary abundance is elevated, and anterograde intraflagellar transport (IFT) is destabilized. Finally, we show that arl-13 interacts genetically with other ciliogenic and ciliary transport–associated genes in maintaining cilium structure/morphology and anterograde IFT stability. Together, these data implicate a role for JS-associated Arl13b at ciliary membranes, where it regulates ciliary transmembrane protein localizations and anterograde IFT assembly stability.

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Kunduri, Govind, Changqing Yuan, Velayoudame Parthibane, Katherine M. Nyswaner, Ritu Kanwar, Kunio Nagashima, Steven G. Britt, et al. "Phosphatidic acid phospholipase A1 mediates ER–Golgi transit of a family of G protein–coupled receptors." Journal of Cell Biology 206, no. 1 (July 7, 2014): 79–95. http://dx.doi.org/10.1083/jcb.201405020.

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The coat protein II (COPII)–coated vesicular system transports newly synthesized secretory and membrane proteins from the endoplasmic reticulum (ER) to the Golgi complex. Recruitment of cargo into COPII vesicles requires an interaction of COPII proteins either with the cargo molecules directly or with cargo receptors for anterograde trafficking. We show that cytosolic phosphatidic acid phospholipase A1 (PAPLA1) interacts with COPII protein family members and is required for the transport of Rh1 (rhodopsin 1), an N-glycosylated G protein–coupled receptor (GPCR), from the ER to the Golgi complex. In papla1 mutants, in the absence of transport to the Golgi, Rh1 is aberrantly glycosylated and is mislocalized. These defects lead to decreased levels of the protein and decreased sensitivity of the photoreceptors to light. Several GPCRs, including other rhodopsins and Bride of sevenless, are similarly affected. Our findings show that a cytosolic protein is necessary for transit of selective transmembrane receptor cargo by the COPII coat for anterograde trafficking.

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Umberger, Nicole L., Tamara Caspary, and Monica Bettencourt-Dias. "Ciliary transport regulates PDGF-AA/αα signaling via elevated mammalian target of rapamycin signaling and diminished PP2A activity." Molecular Biology of the Cell 26, no. 2 (January 15, 2015): 350–58. http://dx.doi.org/10.1091/mbc.e14-05-0952.

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Primary cilia are built and maintained by intraflagellar transport (IFT), whereby the two IFT complexes, IFTA and IFTB, carry cargo via kinesin and dynein motors for anterograde and retrograde transport, respectively. Many signaling pathways, including platelet- derived growth factor (PDGF)-AA/αα, are linked to primary cilia. Active PDGF-AA/αα signaling results in phosphorylation of Akt at two residues: P-AktT308 and P-AktS473, and previous work showed decreased P-AktS473 in response to PDGF-AA upon anterograde transport disruption. In this study, we investigated PDGF-AA/αα signaling via P-AktT308 and P-AktS473 in distinct ciliary transport mutants. We found increased Akt phosphorylation in the absence of PDGF-AA stimulation, which we show is due to impaired dephosphorylation resulting from diminished PP2A activity toward P-AktT308. Anterograde transport mutants display low platelet-derived growth factor receptor (PDGFR)α levels, whereas retrograde mutants exhibit normal PDGFRα levels. Despite this, neither shows an increase in P-AktS473 or P-AktT308 upon PDGF-AA stimulation. Because mammalian target of rapamycin complex 1 (mTORC1) signaling is increased in ciliary transport mutant cells and mTOR signaling inhibits PDGFRα levels, we demonstrate that inhibition of mTORC1 rescues PDGFRα levels as well as PDGF-AA–dependent phosphorylation of AktS473 and AktT308 in ciliary transport mutant MEFs. Taken together, our data indicate that the regulation of mTORC1 signaling and PP2A activity by ciliary transport plays key roles in PDGF-AA/αα signaling.

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Hirokawa, N., R. Sato-Yoshitake, N. Kobayashi, K. K. Pfister, G. S. Bloom, and S. T. Brady. "Kinesin associates with anterogradely transported membranous organelles in vivo." Journal of Cell Biology 114, no. 2 (July 15, 1991): 295–302. http://dx.doi.org/10.1083/jcb.114.2.295.

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Biochemical, pharmacological and immunocytochemical studies have implicated the microtubule-activated ATPase, kinesin, in the movement of membrane bounded organelles in fast axonal transport. In vitro studies suggested that kinesin moves organelles preferentially in the anterograde direction, but data about the function and precise localization of kinesin in the living axon were lacking. The current study was undertaken to establish whether kinesin associates with anterograde or retrograde moving organelles in vivo. Peripheral nerves were ligated to produce accumulations of organelles moving in defined directions. Regions proximal (anterograde) and distal (retrograde) to the ligation were analyzed for kinesin localization by immunofluorescence, and by immunogold electron microscopy using ultracryomicrotomy. Substantial amounts of kinesin were associated with anterograde moving organelles on the proximal side, while significantly less kinesin was detected distally. Statistical analyses indicated that kinesin was mostly associated with membrane-bounded organelles. These observations indicate that axonal kinesin is primarily associated with anterograde moving organelles in vivo.

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Cai, Qian, Claudia Gerwin, and Zu-Hang Sheng. "Syntabulin-mediated anterograde transport of mitochondria along neuronal processes." Journal of Cell Biology 170, no. 6 (September 12, 2005): 959–69. http://dx.doi.org/10.1083/jcb.200506042.

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In neurons, proper distribution of mitochondria in axons and at synapses is critical for neurotransmission, synaptic plasticity, and axonal outgrowth. However, mechanisms underlying mitochondrial trafficking throughout the long neuronal processes have remained elusive. Here, we report that syntabulin plays a critical role in mitochondrial trafficking in neurons. Syntabulin is a peripheral membrane-associated protein that targets to mitochondria through its carboxyl-terminal tail. Using real-time imaging in living cultured neurons, we demonstrate that a significant fraction of syntabulin colocalizes and co-migrates with mitochondria along neuronal processes. Knockdown of syntabulin expression with targeted small interfering RNA or interference with the syntabulin–kinesin-1 heavy chain interaction reduces mitochondrial density within axonal processes by impairing anterograde movement of mitochondria. These findings collectively suggest that syntabulin acts as a linker molecule that is capable of attaching mitochondrial organelles to the microtubule-based motor kinesin-1, and in turn, contributes to anterograde trafficking of mitochondria to neuronal processes.

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von Bartheld, Christopher S., XiaoXia Wang, and Rafal Butowt. "Anterograde Axonal Transport, Transcytosis, and Recycling of Neurotrophic Factors." Molecular Neurobiology 24, no. 1-3 (2001): 001–28. http://dx.doi.org/10.1385/mn:24:1-3:001.

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Kins, Stefan, Silke Hunzelmann, Anita Szodorai, Yung-Hui Kuan, Ulrike Engel, Ulrike Müller, Konrad Beyreuther, Scott Brady, and Gerardo Morfini. "O2-03-03: Assembly of APP anterograde transport vesicles." Alzheimer's & Dementia 6 (July 2010): S101. http://dx.doi.org/10.1016/j.jalz.2010.05.316.

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Nilsson, Elisabeth, and Jan-Olof Karlsson. "Slow anterograde axonal transport of calpain I and II." Neurochemistry International 17, no. 3 (1990): 487–94. http://dx.doi.org/10.1016/0197-0186(90)90032-o.

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Gaynor, Erin C., and Scott D. Emr. "COPI-independent Anterograde Transport: Cargo-selective ER to Golgi Protein Transport in Yeast COPI Mutants." Journal of Cell Biology 136, no. 4 (February 24, 1997): 789–802. http://dx.doi.org/10.1083/jcb.136.4.789.

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The coatomer (COPI) complex mediates Golgi to ER recycling of membrane proteins containing a dilysine retrieval motif. However, COPI was initially characterized as an anterograde-acting coat complex. To investigate the direct and primary role(s) of COPI in ER/Golgi transport and in the secretory pathway in general, we used PCR-based mutagenesis to generate new temperature-conditional mutant alleles of one COPI gene in Saccharomyces cerevisiae, SEC21 (γ-COP). Unexpectedly, all of the new sec21 ts mutants exhibited striking, cargo-selective ER to Golgi transport defects. In these mutants, several proteins (i.e., CPY and α-factor) were completely blocked in the ER at nonpermissive temperature; however, other proteins (i.e., invertase and HSP150) in these and other COPI mutants were secreted normally. Nearly identical cargo-specific ER to Golgi transport defects were also induced by Brefeldin A. In contrast, all proteins tested required COPII (ER to Golgi coat complex), Sec18p (NSF), and Sec22p (v-SNARE) for ER to Golgi transport. Together, these data suggest that COPI plays a critical but indirect role in anterograde transport, perhaps by directing retrieval of transport factors required for packaging of certain cargo into ER to Golgi COPII vesicles. Interestingly, CPY–invertase hybrid proteins, like invertase but unlike CPY, escaped the sec21 ts mutant ER block, suggesting that packaging into COPII vesicles may be mediated by cis-acting sorting determinants in the cargo proteins themselves. These hybrid proteins were efficiently targeted to the vacuole, indicating that COPI is also not directly required for regulated Golgi to vacuole transport. Additionally, the sec21 mutants exhibited early Golgi-specific glycosylation defects and structural aberrations in early but not late Golgi compartments at nonpermissive temperature. Together, these studies demonstrate that although COPI plays an important and most likely direct role both in Golgi–ER retrieval and in maintenance/function of the cis-Golgi, COPI does not appear to be directly required for anterograde transport through the secretory pathway.

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Gaynor, Erin C., Chih-Ying Chen, Scott D. Emr, and Todd R. Graham. "ARF Is Required for Maintenance of Yeast Golgi and Endosome Structure and Function." Molecular Biology of the Cell 9, no. 3 (March 1998): 653–70. http://dx.doi.org/10.1091/mbc.9.3.653.

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ADP ribosylation factor (ARF) is thought to play a critical role in recruiting coatomer (COPI) to Golgi membranes to drive transport vesicle budding. Yeast strains harboring mutant COPI proteins exhibit defects in retrograde Golgi to endoplasmic reticulum protein transport and striking cargo-selective defects in anterograde endoplasmic reticulum to Golgi protein transport. To determine whetherarf mutants exhibit similar phenotypes, the anterograde transport kinetics of multiple cargo proteins were examined inarf mutant cells, and, surprisingly, both COPI-dependent and COPI-independent cargo proteins exhibited comparable defects. Retrograde dilysine-mediated transport also appeared to be inefficient in the arf mutants, and coatomer mutants with no detectable anterograde transport defect exhibited a synthetic growth defect when combined with arf1Δ, supporting a role for ARF in retrograde transport. Remarkably, we found that early and medial Golgi glycosyltransferases localized to abnormally large ring-shaped structures. The endocytic marker FM4–64 also stained similar, but generally larger ring-shaped structures en route from the plasma membrane to the vacuole in arf mutants. Brefeldin A similarly perturbed endosome morphology and also inhibited transport of FM4–64 from endosomal structures to the vacuole. Electron microscopy of arf mutant cells revealed the presence of what appear to be hollow spheres of interconnected membrane tubules which likely correspond to the fluorescent ring structures. Together, these observations indicate that organelle morphology is significantly more affected than transport in the arf mutants, suggesting a fundamental role for ARF in regulating membrane dynamics. Possible mechanisms for producing this dramatic morphological change in intracellular organelles and its relation to the function of ARF in coat assembly are discussed.

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Miranda-Saksena, Monica, Ross A. Boadle, Russell J. Diefenbach, and Anthony L. Cunningham. "Dual Role of Herpes Simplex Virus 1 pUS9 in Virus Anterograde Axonal Transport and Final Assembly in Growth Cones in Distal Axons." Journal of Virology 90, no. 5 (December 23, 2015): 2653–63. http://dx.doi.org/10.1128/jvi.03023-15.

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ABSTRACTThe herpes simplex virus type 1 (HSV-1) envelope protein pUS9 plays an important role in virus anterograde axonal transport and spread from neuronal axons. In this study, we used both confocal microscopy and transmission electron microscopy (TEM) to examine the role of pUS9 in the anterograde transport and assembly of HSV-1 in the distal axon of human and rat dorsal root ganglion (DRG) neurons using US9 deletion (US9−), repair (US9R), and wild-type (strain F, 17, and KOS) viruses. Using confocal microscopy and single and trichamber culture systems, we observed a reduction but not complete block in the anterograde axonal transport of capsids to distal axons as well as a marked (∼90%) reduction in virus spread from axons to Vero cells with the US9 deletion viruses. Axonal transport of glycoproteins (gC, gD, and gE) was unaffected. Using TEM, there was a marked reduction or absence of enveloped capsids, in varicosities and growth cones, in KOS strain and US9 deletion viruses, respectively. Capsids (40 to 75%) in varicosities and growth cones infected with strain 17, F, and US9 repair viruses were fully enveloped compared to less than 5% of capsids found in distal axons infected with the KOS strain virus (which also lacks pUS9) and still lower (<2%) with the US9 deletion viruses. Hence, there was a secondary defect in virus assembly in distal axons in the absence of pUS9 despite the presence of key envelope proteins. Overall, our study supports a dual role for pUS9, first in anterograde axonal transport and second in virus assembly in growth cones in distal axons.IMPORTANCEHSV-1 has evolved mechanisms for its efficient transport along sensory axons and subsequent spread from axons to epithelial cells after reactivation. In this study, we show that deletion of the envelope protein pUS9 leads to defects in virus transport along axons (partial defect) and in virus assembly and egress from growth cones (marked defect). Virus assembly and exit in the neuronal cell body are not impaired in the absence of pUS9. Thus, our findings indicate that pUS9 contributes to the overall HSV-1 anterograde axonal transport, including a major role in virus assembly at the axon terminus, which is not essential in the neuronal cell body. Overall, our data suggest that the process of virus assembly at the growth cones differs from that in the neuronal cell body and that HSV-1 has evolved different mechanisms for virus assembly and exit from different cellular compartments.

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Mueller, Joshua, Catherine A. Perrone, Raqual Bower, Douglas G. Cole, and Mary E. Porter. "The FLA3 KAP Subunit Is Required for Localization of Kinesin-2 to the Site of Flagellar Assembly and Processive Anterograde Intraflagellar Transport." Molecular Biology of the Cell 16, no. 3 (March 2005): 1341–54. http://dx.doi.org/10.1091/mbc.e04-10-0931.

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Intraflagellar transport (IFT) is a bidirectional process required for assembly and maintenance of cilia and flagella. Kinesin-2 is the anterograde IFT motor, and Dhc1b/Dhc2 drives retrograde IFT. To understand how either motor interacts with the IFT particle or how their activities might be coordinated, we characterized a ts mutation in the Chlamydomonas gene encoding KAP, the nonmotor subunit of Kinesin-2. The fla3-1 mutation is an amino acid substitution in a conserved C-terminal domain. fla3-1 strains assemble flagella at 21°C, but cannot maintain them at 33°C. Although the Kinesin-2 complex is present at both 21 and 33°C, the fla3-1 Kinesin-2 complex is not efficiently targeted to or retained in the basal body region or flagella. Video-enhanced DIC microscopy of fla3-1 cells shows that the frequency of anterograde IFT particles is significantly reduced. Anterograde particles move at near wild-type velocities, but appear larger and pause more frequently in fla3-1. Transformation with an epitope-tagged KAP gene rescues all of the fla3-1 defects and results in preferential incorporation of tagged KAP complexes into flagella. KAP is therefore required for the localization of Kinesin-2 at the site of flagellar assembly and the efficient transport of anterograde IFT particles within flagella.

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Lavieu, Gregory, Myun Hwa Dunlop, Alexander Lerich, Hong Zheng, Francesca Bottanelli, and James E. Rothman. "The Golgi ribbon structure facilitates anterograde transport of large cargoes." Molecular Biology of the Cell 25, no. 19 (October 2014): 3028–36. http://dx.doi.org/10.1091/mbc.e14-04-0931.

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In mammalian cells, individual Golgi stacks fuse laterally to form the characteristic perinuclear ribbon structure. Yet the purpose of this remarkable structure has been an enigma. We report that breaking down the ribbon of mammalian cells strongly inhibits intra-Golgi transport of large cargoes without altering the rate of transport of smaller cargoes. In addition, insect cells that naturally harbor dispersed Golgi stacks have limited capacity to transport artificial oversized cargoes. These results imply that the ribbon structure is an essential requirement for transport of large cargoes in mammalian cells, and we suggest that this is because it enables the dilated rims of cisternae (containing the aggregates) to move across the stack as they transfer among adjacent stacks within the ribbon structure.

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Li, Yan, Seung Lim, David Hoffman, Pontus Aspenstrom, Howard J. Federoff, and David A. Rempe. "HUMMR, a hypoxia- and HIF-1α–inducible protein, alters mitochondrial distribution and transport." Journal of Cell Biology 185, no. 6 (June 15, 2009): 1065–81. http://dx.doi.org/10.1083/jcb.200811033.

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Mitochondrial transport is critical for maintenance of normal neuronal function. Here, we identify a novel mitochondria protein, hypoxia up-regulated mitochondrial movement regulator (HUMMR), which is expressed in neurons and is markedly induced by hypoxia-inducible factor 1 α (HIF-1α). Interestingly, HUMMR interacts with Miro-1 and Miro-2, mitochondrial proteins that are critical for mediating mitochondrial transport. Interestingly, knockdown of HUMMR or HIF-1 function in neurons exposed to hypoxia markedly reduces mitochondrial content in axons. Because mitochondrial transport and distribution are inextricably linked, the impact of reduced HUMMR function on the direction of mitochondrial transport was also explored. Loss of HUMMR function in hypoxia diminished the percentage of motile mitochondria moving in the anterograde direction and enhanced the percentage moving in the retrograde direction. Thus, HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. These findings have broad implications for maintenance of neuronal viability and function during physiological and pathological states.

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Fu, Meng-meng, and Erika L. F. Holzbaur. "JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors." Journal of Cell Biology 202, no. 3 (July 29, 2013): 495–508. http://dx.doi.org/10.1083/jcb.201302078.

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Regulation of the opposing kinesin and dynein motors that drive axonal transport is essential to maintain neuronal homeostasis. Here, we examine coordination of motor activity by the scaffolding protein JNK-interacting protein 1 (JIP1), which we find is required for long-range anterograde and retrograde amyloid precursor protein (APP) motility in axons. We identify novel interactions between JIP1 and kinesin heavy chain (KHC) that relieve KHC autoinhibition, activating motor function in single molecule assays. The direct binding of the dynactin subunit p150Glued to JIP1 competitively inhibits KHC activation in vitro and disrupts the transport of APP in neurons. Together, these experiments support a model whereby JIP1 coordinates APP transport by switching between anterograde and retrograde motile complexes. We find that mutations in the JNK-dependent phosphorylation site S421 in JIP1 alter both KHC activation in vitro and the directionality of APP transport in neurons. Thus phosphorylation of S421 of JIP1 serves as a molecular switch to regulate the direction of APP transport in neurons.

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Morris, R. L., and P. J. Hollenbeck. "The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth." Journal of Cell Science 104, no. 3 (March 1, 1993): 917–27. http://dx.doi.org/10.1242/jcs.104.3.917.

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Although small molecules such as ATP diffuse freely in the cytosol, many types of cells nonetheless position their mitochondria in regions of intense ATP consumption. We reasoned that in the highly elongated axonal processes of growing neurons in culture, the active growth cone would form a focus of ATP consumption so distant from the cell body as to require the positioning of mitochondria nearby via regulated axonal transport. To test this hypothesis, we quantified the distribution and transport behavior of mitochondria in live, aerobically respiring chick sympathetic neurons. We found that in the distal region of actively growing axons, the distribution of mitochondria was highly skewed toward the growth cone, with a sevenfold higher density in the region immediately adjacent to the growth cone than in the region 100 microns away. When axonal outgrowth was blocked by substratum-associated barriers or mild cytochalasin E treatment, the gradient of mitochondrial distribution collapsed as mitochondria exited retrogradely from the distal region, becoming uniformly distributed along the axon within one hour. Analysis of individual mitochondrial behaviors revealed that mitochondrial movement everywhere was bidirectional but balanced so that net transport was anterograde in growing axons and retrograde in blocked axons. This reversal in net transport derived from two separate modulations of mitochondrial movement. First, moving mitochondria underwent a transition to a persistently stationary state in the region of active growth cones that was reversed when growth cone activity was halted. Second, the fraction of time that mitochondria spent moving anterogradely was sharply reduced in non-growing axons. Together, these could account for the formation of gradients of mitochondria in growing axons and their dissipation when outgrowth was blocked. This regulated transport behavior was not dependent upon the ability of mitochondria to produce ATP. Our data indicate that mitochondria possess distinct motor activities for both directions of movement and that mitochondrial transport in axons is regulated by both recruitment between stationary and moving states, and direct regulation of the anterograde motor.

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Szodorai, A., Y. H. Kuan, S. Hunzelmann, U. Engel, A. Sakane, T. Sasaki, Y. Takai, et al. "APP Anterograde Transport Requires Rab3A GTPase Activity for Assembly of the Transport Vesicle." Journal of Neuroscience 29, no. 46 (November 18, 2009): 14534–44. http://dx.doi.org/10.1523/jneurosci.1546-09.2009.

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Diefenbach, Russell J., Monica Miranda-Saksena, Eve Diefenbach, David J. Holland, Ross A. Boadle, Patricia J. Armati, and Anthony L. Cunningham. "Herpes Simplex Virus Tegument Protein US11 Interacts with Conventional Kinesin Heavy Chain." Journal of Virology 76, no. 7 (April 1, 2002): 3282–91. http://dx.doi.org/10.1128/jvi.76.7.3282-3291.2002.

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ABSTRACT Little is known about the mechanisms of transport of neurotropic herpesviruses, such as herpes simplex virus (HSV), varicella-zoster virus, and pseudorabies virus, within neurons. For these viruses, which replicate in the nucleus, anterograde transport from the cell body of dorsal root ganglion (DRG) neurons to the axon terminus occurs over long distances. In the case of HSV, unenveloped nucleocapsids in human DRG neurons cocultured with autologous skin were observed by immunoelectron microscopy to colocalize with conventional ubiquitous kinesin, a microtubule-dependent motor protein, in the cell body and axon during anterograde axonal transport. Subsequently, four candidate kinesin-binding structural HSV proteins were identified (VP5, VP16, VP22, and US11) using oligohistidine-tagged human ubiquitous kinesin heavy chain (uKHC) as bait. Of these viral proteins, a direct interaction between uKHC and US11 was identified. In vitro studies identified residues 867 to 894 as the US11-binding site in uKHC located within the proposed heptad repeat cargo-binding domain of uKHC. In addition, the uKHC-binding site in US11 maps to the C-terminal RNA-binding domain. US11 is consistently cotransported with kinetics similar to those of the capsid protein VP5 into the axons of dissociated rat neurons, unlike the other tegument proteins VP16 and VP22. These observations suggest a major role for the uKHC-US11 interaction in anterograde transport of unenveloped HSV nucleocapsids in axons.

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Antal, M., and M. Petkó. "Retrograde transport of the lectin Phaseolus vulgaris leucoagglutinin in frog central nervous system." Journal of Histochemistry & Cytochemistry 38, no. 12 (December 1990): 1913–17. http://dx.doi.org/10.1177/38.12.1701463.

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The transport properties of the lectin Phaseolus vulgaris leucoagglutinin (PHA-L) were tested in the frog central nervous system. After delivery of the lectin to the lower brainstem by iontophoresis, stained axons and axon terminals, as well as neurons with richly arborizing dendrites, were observed indifferent regions of the brain and spinal cord even far away from the site of application. The large number and the Golgi-like appearance of labeled neurons situated rostral and caudal to the site of PHA-L deposit indicate that PHA-L is transported equally in both the anterograde and the retrograde direction in the central nervous system of the frog. This is in contrast with the mammalian nervous system, in which PHA-L is transported predominantly in the anterograde direction and the retrograde transport is poor.

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Seifert, Bianca, Robert Eckenstaler, Raik Rönicke, Julia Leschik, Beat Lutz, Klaus Reymann, Volkmar Lessmann, and Tanja Brigadski. "Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons." Neural Plasticity 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/4145708.

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The neurotrophin brain derived neurotrophic factor (BDNF) is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer’s disease (AD). To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42) treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain.

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Journal articles on the topic 'Anterograde transport'

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