SnapShot: Axonal Transport

University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, USA.
Cell (Impact Factor: 32.24). 05/2012; 149(4):950-950.e1. DOI: 10.1016/j.cell.2012.05.001
Source: PubMed
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Available from: Adam G Hendricks, Jun 16, 2014
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    • "Moreover, we noted an increase in BDNF protein in the DRG, which was reversed by either blockade of retrograde transport or by CRE DNA decoy treatment [18-20], within 3 hrs of IL-6 treatment. These effects are within the time frame permissible from previous measures of retrograde transport [51,52] but are slightly slower than observations made with photactivatable CREB in embryonic DRG neurons in vitro[15]. A very recent study indicated that prior injury can increase anterograde and retrograde transport rates in DRG neurons in vivo and in vitro[53]. "
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    ABSTRACT: Transcriptional regulation of genes by cyclic AMP response element binding protein (CREB) is essential for the maintenance of long-term memory. Moreover, retrograde axonal trafficking of CREB in response to nerve growth factor (NGF) is critical for the survival of developing primary sensory neurons. We have previously demonstrated that hindpaw injection of interleukin-6 (IL-6) induces mechanical hypersensitivity and hyperalgesic priming that is prevented by the local injection of protein synthesis inhibitors. However, proteins that are locally synthesized that might lead to this effect have not been identified. We hypothesized that retrograde axonal trafficking of nascently synthesized CREB might link local, activity-dependent translation to nociceptive plasticity. To test this hypothesis, we determined if IL-6 enhances the expression of CREB and if it subsequently undergoes retrograde axonal transport. IL-6 treatment of sensory neurons in vitro caused an increase in CREB protein and in vivo treatment evoked an increase in CREB in the sciatic nerve consistent with retrograde transport. Importantly, co-injection of IL-6 with the methionine analogue azido-homoalanine (AHA), to assess nascently synthesized proteins, revealed an increase in CREB containing AHA in the sciatic nerve 2 hrs post injection, indicating retrograde transport of nascently synthesized CREB. Behaviorally, blockade of retrograde transport by disruption of microtubules or inhibition of dynein or intrathecal injection of cAMP response element (CRE) consensus sequence DNA oligonucleotides, which act as decoys for CREB DNA binding, prevented the development of IL-6-induced mechanical hypersensitivity and hyperalgesic priming. Consistent with previous studies in inflammatory models, intraplantar IL-6 enhanced the expression of BDNF in dorsal root ganglion (DRG). This effect was blocked by inhibition of retrograde axonal transport and by intrathecal CRE oligonucleotides. Collectively, these findings point to a novel mechanism of axonal translation and retrograde trafficking linking locally-generated signals to long-term nociceptive sensitization.
    Full-text · Article · Jul 2014 · Molecular Pain
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    • "As stated above, communication of a neuronal cell body with distant segments of its axon poses a serious logistical challenge and involves long-distance axonal transport of a wide range of different cargoes including lipids, different protein classes (usually transported via cargo vesicles), organelles as large as mitochondria, but also mRNAs [34,35]. This transport occurs along the axonal MT bundles and is driven by dynein/dynactin and kinesin motor protein dimers/complexes which use pairs of motor domains to step along MTs in a ‘hand-over-hand’ mode at a speed of ≤ 1 μm/s (Additional file 1: Table S1) [34,36]. "
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    ABSTRACT: The hallmarks of neurons are their slender axons which represent the longest cellular processes of animals and which act as the cables that electrically wire the brain, and the brain to the body. Axons extend along reproducible paths during development and regeneration, and they have to be maintained for the life time of an organism. Both axon extension and maintenance essentially depend on the microtubule (MT) cytoskeleton. For this, MTs organise into parallel bundles that are established through extension at the leading axon tips within growth cones, and these bundles then form the architectural backbones, as well as the highways for axonal transport essential for supply and intracellular communication. Axon transport over these enormous distances takes days or even weeks and is a substantial logistic challenge. It is performed by kinesins and dynein / dynactin, which are molecular motors that form close functional links to the MTs they walk along. The intricate machinery which regulates MT dynamics, axonal transport and the motors is essential for nervous system development and function, and its investigation has huge potential to bring urgently required progress in understanding the causes of many developmental and degenerative brain disorders. During the last years new explanations for the highly specific properties of axonal MTs and for their close functional links to motor proteins have emerged, and it has become increasingly clear that motors play active roles also in regulating axonal MT networks. Here, I will provide an overview of these new developments. includes: Table of Drosophila MT motor proteins ( PDF link:
    Full-text · Article · Sep 2013 · Neural Development
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    ABSTRACT: Retrograde axonal transport requires an intricate interaction between the dynein motor and its cargo. What mediates this interaction is largely unknown. Using forward genetics and a novel imaging approach, we identified JNK-interacting protein 3 (Jip3) as a direct mediator of dynein-based retrograde transport of activated (phosphorylated) c-Jun N-terminal Kinase (JNK) and lysosomes. Zebrafish mutants ( ) displayed large axon terminal swellings that contained high levels of activated JNK and lysosomes, but not other retrograde cargos such as late endosomes and autophagosomes. Using analysis of axonal transport, we demonstrated that the terminal accumulations of activated JNK and lysosomes were due to a decreased frequency of retrograde movement of these cargos in , whereas anterograde transport was largely unaffected. Through rescue experiments with Jip3 engineered to lack the JNK binding domain and exogenous expression of constitutively active JNK, we further showed that loss of Jip3-JNK interaction underlies deficits in pJNK retrograde transport, which subsequently caused axon terminal swellings but not lysosome accumulation. Lysosome accumulation, rather, resulted from loss of lysosome association with dynein light intermediate chain (dynein accessory protein) in , as demonstrated by our co-transport analyses. Thus, our results demonstrate that Jip3 is necessary for the retrograde transport of two distinct cargos, active JNK and lysosomes. Furthermore, our data provide strong evidence that Jip3 in fact serves as an adapter protein linking these cargos to dynein.
    Full-text · Article · Feb 2013 · PLoS Genetics
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