SnapShot: Axonal Transport

University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, USA.
Cell (Impact Factor: 33.12). 05/2012; 149(4):950-950.e1. DOI: 10.1016/j.cell.2012.05.001
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Available from: Adam G Hendricks, Jun 16, 2014
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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.
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    ABSTRACT: The extension of long slender axons is a key process of neuronal circuit formation, both during brain development and regeneration. For this, growth cones at the tips of axons are guided towards their correct target cells by signals. Growth cone behaviour downstream of these signals is implemented by their actin and microtubule cytoskeleton. In the first part of this Commentary, we discuss the fundamental roles of the cytoskeleton during axon growth. We present the various classes of actin- and microtubule-binding proteins that regulate the cytoskeleton, and highlight the important gaps in our understanding of how these proteins functionally integrate into the complex machinery that implements growth cone behaviour. Deciphering such machinery requires multidisciplinary approaches, including genetics and the use of simple model organisms. In the second part of this Commentary, we discuss how the application of combinatorial genetics in the versatile genetic model organism Drosophila melanogaster has started to contribute to the understanding of actin and microtubule regulation during axon growth. Using the example of dystonin-linked neuron degeneration, we explain how knowledge acquired by studying axonal growth in flies can also deliver new understanding in other aspects of neuron biology, such as axon maintenance in higher animals and humans.
    Journal of Cell Science 05/2013; 126(11). DOI:10.1242/jcs.126912 · 5.33 Impact Factor
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    ABSTRACT: Axonal transport is the lifeline of axons and synapses. After synthesis in neuronal cell bodies, proteins are conveyed into axons in two distinct rate classes-fast and slow axonal transport. Whereas fast transport delivers vesicular cargoes, slow transport carries cytoskeletal and cytosolic (or soluble) proteins that have critical roles in neuronal structure and function. Although significant progress has been made in dissecting the molecular mechanisms of fast vesicle transport, mechanisms of slow axonal transport are less clear. Why is this so? Historically, conceptual advances in the axonal transport field have paralleled innovations in imaging the movement, and slow-transport cargoes are not as readily seen as motile vesicles. However, new ways of visualizing slow transport have reenergized the field, leading to fundamental insights that have changed our views on axonal transport, motor regulation, and intracellular trafficking in general. This review first summarizes classic studies that characterized axonal transport, and then discusses recent technical and conceptual advances in slow axonal transport that have provided insights into some long-standing mysteries.
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