title: MIM-Induced Membrane Bending Promotes Dendritic Spine Initiation.
abstract: Proper morphogenesis of neuronal dendritic spines is essential for the formation of functional synaptic networks. However, it is not known how spines are initiated. Here, we identify the inverse-BAR (I-BAR) protein MIM/MTSS1 as a nucleator of dendritic spines. MIM accumulated to future spine initiation sites in a PIP2-dependent manner and deformed the plasma membrane outward into a proto-protrusion via its I-BAR domain. Unexpectedly, the initial protrusion formation did not involve actin polymerization. However, PIP2-dependent activation of Arp2/3-mediated actin assembly was required for protrusion elongation. Overexpression of MIM increased the density of dendritic protrusions and suppressed spine maturation. In contrast, MIM deficiency led to decreased density of dendritic protrusions and larger spine heads. Moreover, MIM-deficient mice displayed altered glutamatergic synaptic transmission and compatible behavioral defects. Collectively, our data identify an important morphogenetic pathway, which initiates spine protrusions by coupling phosphoinositide signaling, direct membrane bending, and actin assembly to ensure proper synaptogenesis.
authors.affiliation: Institute of Biotechnology, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland; Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: juha.saarikangas@bc.biol.ethz.ch.
authors.forename: Juha
authors.initials: J
authors.lastname: Saarikangas
authors.affiliation: Université de la Méditerranée, UMR S901 Aix-Marseille 2, Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France.
authors.forename: Nazim
authors.initials: N
authors.lastname: Kourdougli
authors.affiliation: Institute of Biotechnology, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Senju
authors.affiliation: Université de la Méditerranée, UMR S901 Aix-Marseille 2, Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Chazal
authors.affiliation: Department of Biosciences, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Segerstråle
authors.affiliation: Neuroscience Center, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Rimante
authors.initials: R
authors.lastname: Minkeviciene
authors.affiliation: Neuroscience Center, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kuurne
authors.affiliation: Institute of Biotechnology, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Pieta K
authors.initials: PK
authors.lastname: Mattila
authors.affiliation: German Mouse Clinic, Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Lillian
authors.initials: L
authors.lastname: Garrett
authors.affiliation: German Mouse Clinic, Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Chair of Developmental Genetics, Technische Universität München c/o Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, 53105 Bonn, Germany.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Racz
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.affiliation: Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; German Center for Vertigo and Balance Disorders, University Hospital Munich, 81377 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: German Mouse Clinic, Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Chair of Developmental Genetics, Technische Universität München c/o Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Neurodegenerative Diseases, 80336 Munich, Germany; Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, 53105 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Vertigo and Balance Disorders, University Hospital Munich, 81377 Munich, Germany; German Center for Neurodegenerative Diseases, 80336 Munich, Germany; Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Department of Biosciences, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: von Ossowski
authors.affiliation: Faculty of Veterinary Medicine, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Tomi
authors.initials: T
authors.lastname: Taira
authors.affiliation: Institute of Biotechnology, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
authors.affiliation: Université de la Méditerranée, UMR S901 Aix-Marseille 2, Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France; Neuroscience Center, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland. Electronic address: claudio.rivera@helsinki.fi.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivera
authors.affiliation: Neuroscience Center, P.O. Box 56, University of Helsinki, 00014 Helsinki, Finland. Electronic address: pirta.hotulainen@helsinki.fi.
authors.forename: Pirta
authors.initials: P
authors.lastname: Hotulainen
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008959:Models, Neurological; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009415:Nerve Net / Q000254:growth & development / Q000502:physiology / Q000648:ultrastructure; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D014018:Tissue Distribution
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D008840:Microfilament Proteins; C473219:Mtss1 protein, mouse; D009363:Neoplasm Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D012333:RNA, Messenger