title: Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7.
abstract: Specific formation of excitatory and inhibitory synapses is crucial for proper functioning of the brain. Fibroblast growth factor 22 (FGF22) and FGF7 are postsynaptic-cell-derived presynaptic organizers necessary for excitatory and inhibitory presynaptic differentiation, respectively, in the hippocampus. For the establishment of specific synaptic networks, these FGFs must localize to appropriate synaptic locations - FGF22 to excitatory and FGF7 to inhibitory postsynaptic sites. Here, we show that distinct motor and adaptor proteins contribute to intracellular microtubule transport of FGF22 and FGF7. Excitatory synaptic targeting of FGF22 requires the motor proteins KIF3A and KIF17 and the adaptor protein SAP102 (also known as DLG3). By contrast, inhibitory synaptic targeting of FGF7 requires the motor KIF5 and the adaptor gephyrin. Time-lapse imaging shows that FGF22 moves with SAP102, whereas FGF7 moves with gephyrin. These results reveal the basis of selective targeting of the excitatory and inhibitory presynaptic organizers that supports their different synaptogenic functions. Finally, we found that knockdown of SAP102 or PSD95 (also known as DLG4), which impairs the differentiation of excitatory synapses, alters FGF7 localization, suggesting that signals from excitatory synapses might regulate inhibitory synapse formation by controlling the distribution of the inhibitory presynaptic organizer.
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Terauchi
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors.forename: Kendall M
authors.initials: KM
authors.lastname: Timmons
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors.forename: Koto
authors.initials: K
authors.lastname: Kikuma
authors.affiliation: Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, D-20251 Hamburg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pechmann
authors.affiliation: Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, D-20251 Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA hisashi.umemori@childrens.harvard.edu.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Umemori
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D051523:Fibroblast Growth Factor 7 / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C476387:Fgf22 protein, mouse; C496454:Fgf7 protein, mouse; C409642:KIF17 protein, mouse; C490202:Kif3a protein, mouse; D008565:Membrane Proteins; C073441:gephyrin; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D016547:Kinesins
keywords: Excitatory/inhibitory balance; Fibroblast growth factor; Hippocampus; Intracellular microtubule transport; Synapse specificity