The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites.
The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites.
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DOI：
10.1523/jneurosci.3978-12.2013
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发表时间：
2013-04-17
期刊：
影响因子：
--
通讯作者：
Tolias KF
中科院分区：
文献类型：
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作者：
Duman JG;Tzeng CP;Tu YK;Munjal T;Schwechter B;Ho TS;Tolias KF
兴奋性突触是主要存在于大脑树突棘上的极化结构。小 GTPase Rac1 通过调节肌动蛋白动力学来调节突触和棘的发育和可塑性。通过将 Rac1-鸟嘌呤核苷酸交换因子 Tiam1 限制在刺上，极性蛋白 Par3 通过空间控制 Rac1 激活来促进突触发育。然而，将 Par3 招募到脊柱的机制尚不清楚。在这里，我们将大脑特异性血管生成抑制剂 1 (BAI1) 确定为一种突触粘附 GPCR，是小鼠和大鼠的棘发生和突触发生所必需的。我们发现 BAI1 与 Par3/Tiam1 相互作用并将这些蛋白质招募到突触位点。 BAI1 敲低会导致 Par3/Tiam1 错误定位，并导致激活的 Rac1 和丝状肌动蛋白从棘中丢失。有趣的是，BAI1 还通过与不同的 Rac1-鸟嘌呤核苷酸交换因子模块 ELMO/DOCK180 相互作用，介导专业吞噬细胞中的 Rac 依赖性吞噬。然而，这种相互作用对于 BAI1 在突触发育中的作用是可有可无的，因为不能与 ELMO/DOCK180 相互作用的 BAI1 突变体可以挽救 BAI1 敲低神经元中的脊柱缺陷，而不能与 Par3/Tiam1 相互作用的突变体既不能挽救脊柱缺陷，也不能挽救 Par3 定位。此外，Tiam1 的过度表达可挽救 BAI1 敲低脊柱表型。这些结果表明 BAI1 在突触发生中发挥着重要作用，其机制与其在吞噬作用中的作用不同。此外，我们的结果提供了第一个将 PAR 极性复合体成员靶向突触的细胞表面受体的例子。
Excitatory synapses are polarized structures that primarily reside on dendritic spines in the brain. The small GTPase Rac1 regulates the development and plasticity of synapses and spines by modulating actin dynamics. By restricting the Rac1-guanine nucleotide exchange factor Tiam1 to spines, the polarity protein Par3 promotes synapse development by spatially controlling Rac1 activation. However, the mechanism for recruiting Par3 to spines is unknown. Here, we identify brain-specific angiogenesis inhibitor 1 (BAI1) as a synaptic adhesion GPCR that is required for spinogenesis and synaptogenesis in mice and rats. We show that BAI1 interacts with Par3/Tiam1 and recruits these proteins to synaptic sites. BAI1 knockdown results in Par3/Tiam1 mislocalization and loss of activated Rac1 and filamentous actin from spines. Interestingly, BAI1 also mediates Rac-dependent engulfment in professional phagocytes through its interaction with a different Rac1-guanine nucleotide exchange factor module, ELMO/DOCK180. However, this interaction is dispensable for BAI1’s role in synapse development because a BAI1 mutant that cannot interact with ELMO/DOCK180 rescues spine defects in BAI1-knockdown neurons, whereas a mutant that cannot interact with Par3/Tiam1 rescues neither spine defects nor Par3 localization. Further, overexpression of Tiam1 rescues BAI1 knockdown spine phenotypes. These results indicate that BAI1 plays an important role in synaptogenesis that is mechanistically distinct from its role in phagocytosis. Furthermore, our results provide the first example of a cell surface receptor that targets members of the PAR polarity complex to synapses.