Interleukin-1 Receptor Accessory Protein Organizes Neuronal Synaptogenesis as a Cell Adhesion Molecule
Interleukin-1 Receptor Accessory Protein Organizes Neuronal Synaptogenesis as a Cell Adhesion Molecule
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DOI：
10.1523/jneurosci.4637-11.2012
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发表时间：
2012-02-22
影响因子：
5.3
通讯作者：
Mishina, Masayoshi
中科院分区：
文献类型：
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作者：
Yoshida, Tomoyuki;Shiroshima, Tomoko;Mishina, Masayoshi
白细胞介素-1受体辅助蛋白（IL-1 RAcP）是介导对白细胞介素-1家族细胞因子的免疫应答的受体复合物的重要组成部分。IL-1 RAcP在脑中以两种亚型存在，IL-1 RAcP和IL-1 RAcPb，仅在C-末端区域不同。在这里，我们发现强大的突触活性IL-1 RAcP在培养的皮层神经元。敲低IL-1 RAcP异构体在培养的皮层神经元抑制突触的形成所示的活性区蛋白巴松点和树突状突起的减少。IL-1 RAcP恢复了突触前巴松管点的积累，而IL-1 RAcPb拯救了巴松管点和树突突起。因此，IL-1 RAcP在皮层神经元中的表达促进了Bassoon puncta的积累，而IL-1 RAcPb的表达促进了Bassoon puncta的积累和棘的发生。IL-1 RAcP通过胞外结构域与蛋白酪氨酸磷酸酶（PTP）δ相互作用。PTP δ剪接变体Ig样结构域中的小外显子肽对于它们与IL-1 RAcP的有效结合至关重要。在PTP δ基因敲除小鼠的皮质神经元中，IL-1 RAcP亚型的突触形成活性减弱。相应地，PTP δ需要IL-1 RAcPb诱导突触后分化。因此，IL-1 RAcPb双向调节皮层神经元的突触形成。此外，皮质和海马锥体神经元的棘密度降低IL-1 RAcP基因敲除小鼠缺乏这两种亚型。这些结果表明，IL-1 RAcP亚型作为跨突触细胞粘附分子在脑中发挥作用，并组织突触形成。因此，IL-1 RAcP代表了免疫系统和脑中突触形成之间有趣的分子联系。
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) delta through the extracellular domain. Mini-exon peptides in the Ig-like domains of PTP delta splice variants were critical for their efficient binding to IL-1RAcP. The synaptogenic activities of IL-1RAcP isoforms were diminished in cortical neurons from PTP delta knock-out mice. Correspondingly, PTP delta 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.