title: Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule.
abstract: Interleukin-1 receptor accessory protein (IL-1RAcP) is the essential component of receptor complexes mediating immune responses to interleukin-1 family cytokines. IL-1RAcP in the brain exists in two isoforms, IL-1RAcP and IL-1RAcPb, differing only in the C-terminal region. Here, we found robust synaptogenic activities of IL-1RAcP in cultured cortical neurons. Knockdown of IL-1RAcP isoforms in cultured cortical neurons suppressed synapse formation as indicated by decreases of active zone protein Bassoon puncta and dendritic protrusions. IL-1RAcP recovered the accumulation of presynaptic Bassoon puncta, while IL-1RAcPb rescued both Bassoon puncta and dendritic protrusions. Consistently, the expression of IL-1RAcP in cortical neurons enhances the accumulation of Bassoon puncta and that of IL-1RAcPb stimulated both Bassoon puncta accumulation and spinogenesis. IL-1RAcP interacted with protein tyrosine phosphatase (PTP) δ through the extracellular domain. Mini-exon peptides in the Ig-like domains of PTPδ splice variants were critical for their efficient binding to IL-1RAcP. The synaptogenic activities of IL-1RAcP isoforms were diminished in cortical neurons from PTPδ knock-out mice. Correspondingly, PTPδ required IL-1RAcPb to induce postsynaptic differentiation. Thus, IL-1RAcPb bidirectionally regulated synapse formation of cortical neurons. Furthermore, the spine densities of cortical and hippocampal pyramidal neurons were reduced in IL-1RAcP knock-out mice lacking both isoforms. These results suggest that IL-1RAcP isoforms function as trans-synaptic cell adhesion molecules in the brain and organize synapse formation. Thus, IL-1RAcP represents an interesting molecular link between immune systems and synapse formation in the brain.
authors.affiliation: Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shiroshima
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Misato
authors.initials: M
authors.lastname: Yasumura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uemura
authors.forename: Xigui
authors.initials: X
authors.lastname: Chen
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
mesh_terms: D000596:Amino Acids; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D005347:Fibroblasts / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000145:classification / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000172:deficiency; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D013569:Synapses / Q000502:physiology*; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D053577:Interleukin-1 Receptor Accessory Protein; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C098463:dolaisoleucine; C493406:vesicular GABA transporter; D049452:Green Fluorescent Proteins; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4