title: Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.
abstract: The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Sonal
authors.initials: S
authors.lastname: Thakar
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Ting
authors.initials: T
authors.lastname: Yu
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Mao
authors.initials: M
authors.lastname: Ye
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Onishi
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: John
authors.initials: J
authors.lastname: Scott
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Qi
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Catarina
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Darwin K
authors.initials: DK
authors.lastname: Berg
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093; yzou@ucsd.edu.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Zou
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D016764:Cell Polarity; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D008124:Locomotion; D008297:Male; D018782:Maze Learning; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D000071818:Wnt-5a Protein / Q000502:physiology
chemical_list: D015820:Cadherins; C444454:Celsr3 protein, mouse; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D018698:Glutamic Acid
keywords: Celsr3; Vangl2; glutamatergic; synapse formation