PDF(Pubmed)
Abstract：
In the developing human brain, only 53 stochastically expressed clustered protocadherin (cPcdh) isoforms enable neurites from individual neurons to recognize and self-avoid while simultaneously maintaining contact with neurites from other neurons. Cell assays have demonstrated that self-recognition occurs only when all cPcdh isoforms perfectly match across the cell boundary, with a single mismatch in the cPcdh expression profile interfering with recognition. It remains unclear, however, how a single mismatched isoform between neighboring cells is sufficient to block erroneous recognitions. Using systematic cell aggregation experiments, we show that abolishing cPcdh interactions on the same membrane (cis) results in a complete loss of specific combinatorial binding between cells (trans). Our computer simulations demonstrate that the organization of cPcdh in linear array oligomers, composed of cis and trans interactions, enhances self-recognition by increasing the concentration and stability of cPcdh trans complexes between the homotypic membranes. Importantly, we show that the presence of mismatched isoforms between cells drastically diminishes the concentration and stability of the trans complexes. Overall, we provide an explanation for the role of the cPcdh assembly arrangements in neuronal self/non-self-discrimination underlying neuronal self-avoidance.
摘要：
在发育中的人脑中，只有53个随机表达的簇状原钙粘蛋白（cPcdh）同工型使单个神经元的神经突能够识别和自我避免，同时与其他神经元的神经突保持接触。细胞实验表明，只有当所有cPcdh同工型在细胞边界上完全匹配时，才会发生自我识别。cPcdh表达谱中的单个错配干扰识别。目前还不清楚,然而,相邻细胞之间的单个不匹配同工型如何足以阻止错误的识别。使用系统的细胞聚集实验，我们表明，消除cPcdh相互作用在相同的膜（顺式）导致细胞之间的特异性组合结合（反式）的完全丧失。我们的计算机模拟表明，线性阵列低聚物中cPcdh的组织，由顺式和反式相互作用组成，通过增加同型膜之间cPcdh反式复合物的浓度和稳定性来增强自我识别。重要的是,我们发现细胞间错配同工型的存在会显著降低反式复合物的浓度和稳定性。总的来说,我们解释了cPcdh组装排列在神经元自我/非自我区分中的作用，这些神经元自我回避。
