title: Drosophila Syd-1, liprin-α, and protein phosphatase 2A B' subunit Wrd function in a linear pathway to prevent ectopic accumulation of synaptic materials in distal axons.
abstract: During synaptic development, presynaptic differentiation occurs as an intrinsic property of axons to form specialized areas of plasma membrane [active zones (AZs)] that regulate exocytosis and endocytosis of synaptic vesicles. Genetic and biochemical studies in vertebrate and invertebrate model systems have identified a number of proteins involved in AZ assembly. However, elucidating the molecular events of AZ assembly in a spatiotemporal manner remains a challenge. Syd-1 (synapse defective-1) and Liprin-α have been identified as two master organizers of AZ assembly. Genetic and imaging analyses in invertebrates show that Syd-1 works upstream of Liprin-α in synaptic assembly through undefined mechanisms. To understand molecular pathways downstream of Liprin-α, we performed a proteomic screen of Liprin-α-interacting proteins in Drosophila brains. We identify Drosophila protein phosphatase 2A (PP2A) regulatory subunit B' [Wrd (Well Rounded)] as a Liprin-α-interacting protein, and we demonstrate that it mediates the interaction of Liprin-α with PP2A holoenzyme and the Liprin-α-dependent synaptic localization of PP2A. Interestingly, loss of function in syd-1, liprin-α, or wrd shares a common defect in which a portion of synaptic vesicles, dense-core vesicles, and presynaptic cytomatrix proteins ectopically accumulate at the distal, but not proximal, region of motoneuron axons. Strong genetic data show that a linear syd-1/liprin-α/wrd pathway in the motoneuron antagonizes glycogen synthase kinase-3β kinase activity to prevent the ectopic accumulation of synaptic materials. Furthermore, we provide data suggesting that the syd-1/liprin-α/wrd pathway stabilizes AZ specification at the nerve terminal and that such a novel function is independent of the roles of syd-1/liprin-α in regulating the morphology of the T-bar structural protein BRP (Bruchpilot).
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors.forename: Dinara
authors.initials: D
authors.lastname: Bulgari
authors.affiliation: Institute for Biology/Genetics, Free University of Berlin, D-14195 Berlin, Germany, and.
authors.forename: Mathias A
authors.initials: MA
authors.lastname: Böhme
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Goettfert
authors.affiliation: Institute for Biology/Genetics, Free University of Berlin, D-14195 Berlin, Germany, and.
authors.forename: Carolin
authors.initials: C
authors.lastname: Wichmann
authors.affiliation: Institute for Biology/Genetics, Free University of Berlin, D-14195 Berlin, Germany, and.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sigrist
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Levitan
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, cwu@lsuhsc.edu.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000737:chemistry / Q000502:physiology*; D002828:Choristoma / Q000378:metabolism; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster; D020690:GTPase-Activating Proteins / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D055550:Protein Stability; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490600:Liprin-alpha protein, Drosophila; D010750:Phosphoproteins; C548043:RhoGAP100F protein, Drosophila; D010749:Phosphoprotein Phosphatases; C079898:tws protein, Drosophila
keywords: Drosophila; Liprin-alpha; PP2A; Syd-1; active zone assembly; presynaptic differentiation