Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation
Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation
复制标题
鉴定 O 型蛋白酪氨酸磷酸酶受体 (PTPRO) 作为促进突触形成的突触粘附分子。
DOI：
10.1523/jneurosci.0729-17.2017
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发表时间：
2017-10-11
影响因子：
5.3
通讯作者：
Zhang, Chen
中科院分区：
文献类型：
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作者：
Jiang, Wei;Wei, Mengping;Zhang, Chen
突触是两个神经元之间形成的特化单一结构，其正确形成对于介导大脑中的信息流至关重要。人们认为突触细胞黏附分子（CAMs）参与了突触形成过程的起始。然而，体内功能分析表明，大多数知名的突触CAMs调节的是突触成熟和可塑性，而非突触形成，这表明要么CAMs在突触形成过程中协同发挥作用，要么还有更多的CAMs有待发现。通过利用共培养系统筛选未知的CAMs，我们发现蛋白酪氨酸磷酸酶受体O型（PTPRO）是一种强效的CAM，无论性别，它能在人胚肾293细胞与新生小鼠海马神经元的共培养中诱导人工突触簇的形成。PTPRO在小鼠大脑中富集，并定位于兴奋性突触的突触后位点。在培养的海马神经元中过表达PTPRO会增加突触数量和微小兴奋性突触后电流（mEPSCs）的频率。通过短发夹RNA（shRNA）敲低培养神经元中PTPRO的表达，会减少突触数量和mEPSCs的频率。表达全长PTPRO或缺失胞质结构域的截短型PTPRO，均可挽救shRNA敲低所产生的影响。与这些结果一致的是，在共培养实验中，PTPRO的N端胞外结构域是其突触发生活性所必需的。我们的数据表明，PTPRO是一种突触CAM，可作为兴奋性突触形成的强效起始因子。
The proper formation of synapses-specialized unitary structures formed between two neurons-is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in vivo functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock-down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses.