Department of Neuroscience, Tufts University, Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts 02111, USA.
J Neurosci. 2010 Aug 18;30(33):11073-85. doi: 10.1523/JNEUROSCI.0983-10.2010.
Synaptic efficacy requires that presynaptic and postsynaptic specializations align precisely and mature coordinately. The underlying mechanisms are poorly understood, however. We propose that adenomatous polyposis coli protein (APC) is a key coordinator of presynaptic and postsynaptic maturation. APC organizes a multiprotein complex that directs nicotinic acetylcholine receptor (nAChR) localization at postsynaptic sites in avian ciliary ganglion neurons in vivo. We hypothesize that the APC complex also provides retrograde signals that direct presynaptic active zones to develop in register with postsynaptic nAChR clusters. In our model, the APC complex provides retrograde signals via postsynaptic neuroligin that interacts extracellularly with presynaptic neurexin. S-SCAM (synaptic cell adhesion molecule) and PSD-93 (postsynaptic density-93) are scaffold proteins that bind to neuroligin. We identify S-SCAM as a novel component of neuronal nicotinic synapses. We show that S-SCAM, PSD-93, neuroligin and neurexin are enriched at alpha3*-nAChR synapses. PSD-93 and S-SCAM bind to APC and its binding partner beta-catenin, respectively. Blockade of selected APC and beta-catenin interactions, in vivo, leads to decreased postsynaptic accumulation of S-SCAM, but not PSD-93. Importantly, neuroligin synaptic clusters are also decreased. On the presynaptic side, there are decreases in neurexin and active zone proteins. Further, presynaptic terminals are less mature structurally and functionally. We define a novel neural role for APC by showing that the postsynaptic APC multiprotein complex is required for anchoring neuroligin and neurexin at neuronal synapses in vivo. APC human gene mutations correlate with autism spectrum disorders, providing strong support for the importance of the association, demonstrated here, between APC, neuroligin and neurexin.
突触效能要求突触前和突触后特化精确对齐并协调成熟。然而，其潜在机制尚不清楚。我们提出腺瘤性结肠息肉病蛋白（APC）是突触前和突触后成熟的关键协调蛋白。APC 组织了一个多蛋白复合物，该复合物可在体内引导禽类睫状神经节神经元的烟碱型乙酰胆碱受体（nAChR）定位到突触后部位。我们假设 APC 复合物还提供逆行信号，以指导突触前活性区与突触后 nAChR 簇精确对齐发育。在我们的模型中，APC 复合物通过与突触前神经连接蛋白相互作用的突触后神经黏连蛋白提供逆行信号。S-SCAM（突触细胞黏附分子）和 PSD-93（突触后密度蛋白-93）是与神经黏连蛋白结合的支架蛋白。我们确定 S-SCAM 为神经元烟碱型乙酰胆碱受体突触的新组成部分。我们发现 S-SCAM、PSD-93、神经黏连蛋白和神经连接蛋白在 alpha3*-nAChR 突触中丰富存在。PSD-93 和 S-SCAM 分别与 APC 及其结合伴侣β-连环蛋白结合。体内阻断 APC 和β-连环蛋白的选择相互作用会导致 S-SCAM 在后突触中的积累减少，但 PSD-93 不会减少。重要的是，神经黏连蛋白突触簇也减少了。在突触前侧，神经连接蛋白和活性区蛋白减少。此外，突触前末梢在结构和功能上不太成熟。通过显示突触后 APC 多蛋白复合物是体内锚定神经元突触中神经黏连蛋白和神经连接蛋白所必需的，我们定义了 APC 的新的神经作用。APC 人类基因突变与自闭症谱系障碍相关，为这里显示的 APC、神经黏连蛋白和神经连接蛋白之间的关联提供了强有力的支持。
