title: A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons.
abstract: Notch signaling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Although recent studies implicate that Notch regulates synaptic plasticity or cognitive performance, the molecular mechanism how Notch works in mature neurons remains uncertain. Here we demonstrate that a novel Notch signaling is involved in expression of synaptic proteins in postmitotic neurons. Levels of several synaptic vesicle proteins including synaptophysin 1 and VGLUT1 were increased when neurons were cocultured with Notch ligands-expressing NIH3T3 cells. Neuron-specific deletion of Notch genes decreased these proteins, suggesting that Notch signaling maintains the expression of synaptic vesicle proteins in a cell-autonomous manner. Unexpectedly, cGMP-dependent protein kinase (PKG) inhibitor, but not γ-secretase inhibitor, abolished the elevation of synaptic vesicle proteins, suggesting that generation of Notch intracellular domain is dispensable for this function. These data uncover a ligand-dependent, but γ-secretase-independent, non-canonical Notch signaling involved in presynaptic protein expression in postmitotic neurons.
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.|Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical School, Kansas City, KS 66160, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimune
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Kanagawa 259-1193, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.affiliation: Division of Mammalian Development, National Institute of Genetics, Shizuoka 411-8540, Japan.|Department of Genetics, SOKENDAI, Shizuoka 411-8540, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Harada
authors.affiliation: Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D051379:Mice; D008938:Mitosis; D041681:NIH 3T3 Cells; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013572:Synaptic Vesicles / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism*; D015854:Up-Regulation; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism*
chemical_list: D051880:Receptors, Notch; C493465:Slc17a7 protein, mouse; D016708:Synaptophysin; C569015:Syp protein, mouse; D050598:Vesicular Glutamate Transport Protein 1