title: MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses through Neuroligin.
abstract: At synapses, the presynaptic release machinery is precisely juxtaposed to the postsynaptic neurotransmitter receptors. We studied the molecular mechanisms underlying this exquisite alignment at the C. elegans inhibitory synapses. We found that the sole C. elegans neuroligin homolog, NLG-1, localizes specifically at GABAergic postsynapses and is required for clustering the GABA(A) receptor UNC-49. Two presynaptic factors, Punctin/MADD-4, an ADAMTS-like extracellular protein, and neurexin/NRX-1, act partially redundantly to recruit NLG-1 to synapses. In the absence of both MADD-4 and NRX-1, NLG-1 and GABA(A) receptors fail to cluster, and GABAergic synaptic transmission is severely compromised. Biochemically, we detect an interaction between MADD-4 and NLG-1, as well as between MADD-4 and NRX-1. Interestingly, the presence of NRX-1 potentiates binding between Punctin/MADD-4 and NLG-1, suggestive of a tripartite receptor ligand complex. We propose that presynaptic terminals induce postsynaptic receptor clustering through the action of both secreted ECM proteins and trans-synaptic adhesion complexes.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Géraldine S
authors.initials: GS
authors.lastname: Maro
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
authors.forename: Shangbang
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Agnieszka M
authors.initials: AM
authors.lastname: Olechwier
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
authors.forename: Wesley L
authors.initials: WL
authors.lastname: Hung
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Engin
authors.initials: E
authors.lastname: Özkan
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada. Electronic address: zhen@lunenfeld.ca.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhen
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: kangshen@stanford.edu.
authors.forename: Kang
authors.initials: K
authors.lastname: Shen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D059330:GABAergic Neurons / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000502:physiology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008164:Luminescent Proteins; C568399:MADD-4 protein, C elegans; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D016212:Transforming Growth Factor beta; C113622:UNC-129 protein, C elegans; C093438:neuroligin 1; C574757:nrx-1 protein, C elegans