title: Presynaptic spinophilin tunes neurexin signalling to control active zone architecture and function.
abstract: Assembly and maturation of synapses at the Drosophila neuromuscular junction (NMJ) depend on trans-synaptic neurexin/neuroligin signalling, which is promoted by the scaffolding protein Syd-1 binding to neurexin. Here we report that the scaffold protein spinophilin binds to the C-terminal portion of neurexin and is needed to limit neurexin/neuroligin signalling by acting antagonistic to Syd-1. Loss of presynaptic spinophilin results in the formation of excess, but atypically small active zones. Neuroligin-1/neurexin-1/Syd-1 levels are increased at spinophilin mutant NMJs, and removal of single copies of the neurexin-1, Syd-1 or neuroligin-1 genes suppresses the spinophilin-active zone phenotype. Evoked transmission is strongly reduced at spinophilin terminals, owing to a severely reduced release probability at individual active zones. We conclude that presynaptic spinophilin fine-tunes neurexin/neuroligin signalling to control active zone number and functionality, thereby optimizing them for action potential-induced exocytosis.
authors.affiliation: Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, Berlin 14195, Germany.|NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Karzan
authors.initials: K
authors.lastname: Muhammad
authors.affiliation: Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, Berlin 14195, Germany.|NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Suneel
authors.initials: S
authors.lastname: Reddy-Alla
authors.affiliation: Freie Universität Berlin, Institut für Chemie und Biochemie /Strukturbiochmie, Takustrasse 6, Berlin D-14195, Germany.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Driller
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50-70, Basel 4056, Switzerland.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schreiner
authors.affiliation: NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Ulises
authors.initials: U
authors.lastname: Rey
authors.affiliation: NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Mathias A
authors.initials: MA
authors.lastname: Böhme
authors.affiliation: NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hollmann
authors.affiliation: Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, Berlin 14195, Germany.
authors.forename: Niraja
authors.initials: N
authors.lastname: Ramesh
authors.affiliation: Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, Berlin 14195, Germany.|NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Depner
authors.affiliation: NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Lützkendorf
authors.affiliation: Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, Berlin 14195, Germany.|NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Matkovic
authors.affiliation: Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, Berlin 14195, Germany.|NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Götz
authors.affiliation: NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Dominique D
authors.initials: DD
authors.lastname: Bergeron
authors.affiliation: Freie Universität Berlin, Institut für Chemie und Biochemie /Strukturbiochmie, Takustrasse 6, Berlin D-14195, Germany.|Leibniz Institut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, Berlin 13125, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmoranzer
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Goettfert
authors.affiliation: VIB Center for the Biology of Disease, Herestraat 49, Leuven 3000, Belgium.
authors.forename: Mathew
authors.initials: M
authors.lastname: Holt
authors.affiliation: Freie Universität Berlin, Institut für Chemie und Biochemie /Strukturbiochmie, Takustrasse 6, Berlin D-14195, Germany.
authors.forename: Markus C
authors.initials: MC
authors.lastname: Wahl
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Hell
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50-70, Basel 4056, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Scheiffele
authors.affiliation: NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.|Leibniz Institut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, Berlin 13125, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Walter
authors.affiliation: Freie Universität Berlin, Institut für Chemie und Biochemie /Strukturbiochmie, Takustrasse 6, Berlin D-14195, Germany.
authors.forename: Bernhard
authors.identifier: http://orcid.org/0000-0001-7928-4488
authors.initials: B
authors.lastname: Loll
authors.affiliation: Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, Berlin 14195, Germany.|NeuroCure, Charité, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sigrist
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D054731:PDZ Domains; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D000099273:Neurabins
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D000099273:Neurabins; C491321:Nrx protein, Drosophila; C548043:RhoGAP100F protein, Drosophila; C093438:neuroligin 1