title: A PIK3C3-ankyrin-B-dynactin pathway promotes axonal growth and multiorganelle transport.
abstract: Axon growth requires long-range transport of organelles, but how these cargoes recruit their motors and how their traffic is regulated are not fully resolved. In this paper, we identify a new pathway based on the class III PI3-kinase (PIK3C3), ankyrin-B (AnkB), and dynactin, which promotes fast axonal transport of synaptic vesicles, mitochondria, endosomes, and lysosomes. We show that dynactin associates with cargo through AnkB interactions with both the dynactin subunit p62 and phosphatidylinositol 3-phosphate (PtdIns(3)P) lipids generated by PIK3C3. AnkB knockout resulted in shortened axon tracts and marked reduction in membrane association of dynactin and dynein, whereas it did not affect the organization of spectrin-actin axonal rings imaged by 3D-STORM. Loss of AnkB or of its linkages to either p62 or PtdIns(3)P or loss of PIK3C3 all impaired organelle transport and particularly retrograde transport in hippocampal neurons. Our results establish new functional relationships between PIK3C3, dynactin, and AnkB that together promote axonal transport of organelles and are required for normal axon length.
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815 Department of Biochemistry and Department of Radiology, Duke University, Durham, NC 27708.
authors.forename: Damaris Nadia
authors.initials: DN
authors.lastname: Lorenzo
authors.affiliation: Department of Biochemistry and Department of Radiology, Duke University, Durham, NC 27708.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Badea
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815 Department of Biochemistry and Department of Radiology, Duke University, Durham, NC 27708.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Davis
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815 Department of Biochemistry and Department of Radiology, Duke University, Durham, NC 27708.
authors.forename: Janell
authors.initials: J
authors.lastname: Hostettler
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815 Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138 Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815 Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138 Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138.
authors.forename: Guisheng
authors.initials: G
authors.lastname: Zhong
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815 Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138 Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815 Department of Biochemistry and Department of Radiology, Duke University, Durham, NC 27708 vann.bennett@dm.duke.edu.
authors.forename: Vann
authors.initials: V
authors.lastname: Bennett
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000378:metabolism*; D001370:Axonal Transport; D001369:Axons / Q000502:physiology*; D049108:Cell Enlargement; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000072159:Dynactin Complex; D005260:Female; D006624:Hippocampus / Q000166:cytology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D015388:Organelles / Q000378:metabolism
chemical_list: C498995:Ank2 protein, mouse; D017487:Ankyrins; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D058546:Class III Phosphatidylinositol 3-Kinases