title: The Dynamic Localization of Cytoplasmic Dynein in Neurons Is Driven by Kinesin-1.
abstract: Cytoplasmic dynein, the major motor driving retrograde axonal transport, must be actively localized to axon terminals. This localization is critical as dynein powers essential retrograde trafficking events required for neuronal survival, such as neurotrophic signaling. Here, we demonstrate that the outward transport of dynein from soma to axon terminal is driven by direct interactions with the anterograde motor kinesin-1. In developing neurons, we find that dynein dynamically cycles between neurites, following kinesin-1 and accumulating in the nascent axon coincident with axon specification. In established axons, dynein is constantly transported down the axon at slow axonal transport speeds; inhibition of the kinesin-1-dynein interaction effectively blocks this process. In vitro and live-imaging assays to investigate the underlying mechanism lead us to propose a new model for the slow axonal transport of cytosolic cargos, based on short-lived direct interactions of cargo with a highly processive anterograde motor. VIDEO ABSTRACT.
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA; Molecular NeuroPathobiology Laboratory, Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Twelvetrees
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, SE1 1UL, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pernigo
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, SE1 1UL, UK.
authors.forename: Anneri
authors.initials: A
authors.lastname: Sanger
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Guedes-Dias
authors.affiliation: Molecular NeuroPathobiology Laboratory, Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, SE1 1UL, UK.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Steiner
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, SE1 1UL, UK.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Dodding
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA. Electronic address: holzbaur@mail.med.upenn.edu.
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
mesh_terms: D000818:Animals; D001370:Axonal Transport; D002478:Cells, Cultured; D056445:Cytoplasmic Dyneins / Q000378:metabolism*; D004398:Dyneins / Q000235:genetics / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism*; D051379:Mice; D016501:Neurites / Q000378:metabolism
chemical_list: D056445:Cytoplasmic Dyneins; D004398:Dyneins; D016547:Kinesins