Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule

• Published in: The Journal of neuroscience Vol. 32; no. 8; pp. 2588 - 2600
• Main Authors: Yoshida, Tomoyuki, Shiroshima, Tomoko, Lee, Sung-Jin, Yasumura, Misato, Uemura, Takeshi, Chen, Xigui, Iwakura, Yoichiro, Mishina, Masayoshi
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 22.02.2012
• Subjects: Amino Acids; Animals; Animals, Newborn; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cells, Cultured; Cerebral Cortex - cytology; Coculture Techniques; Fibroblasts - physiology; Green Fluorescent Proteins - genetics; Humans; Interleukin-1 Receptor Accessory Protein - classification; Interleukin-1 Receptor Accessory Protein - genetics; Interleukin-1 Receptor Accessory Protein - physiology; Mice; Mice, Knockout; Neural Cell Adhesion Molecules - genetics; Neural Cell Adhesion Molecules - metabolism; Neurons - cytology; Neurons - physiology; Presynaptic Terminals - physiology; Protein Binding - genetics; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Structure, Tertiary - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 4 - deficiency; RNA, Small Interfering - metabolism; Signal Transduction; Surface Plasmon Resonance; Synapses - physiology; Transfection; Vesicular Glutamate Transport Protein 1 - metabolism; Vesicular Inhibitory Amino Acid Transport Proteins - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.4637-11.2012

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.