The Down syndrome cell adhesion molecule (DSCAM) belongs to the immunoglobulin superfamily (IgSF) and plays important roles in neural development. It has a large ectodomain, including 10 Ig-like domains and 6 fibronectin III (FnIII) domains. Previous data have shown that DSCAM can mediate cell adhesion by forming homophilic dimers between cells and contributes to self-avoidance of neurites or neuronal tiling, which is important for neural network formation. However, the organization and assembly of DSCAM at cell adhesion interfaces has not been fully understood. Here we combine electron microscopy and other biophysical methods to characterize the structure of the DSCAM-mediated cell adhesion and generate three-dimensional views of the adhesion interfaces of DSCAM by electron tomography. The results show that mouse DSCAM forms a regular pattern at the adhesion interfaces. The Ig-like domains contribute to both trans homophilic interactions and cis assembly of the pattern, and the FnIII domains are crucial for the cis pattern formation as well as the interaction with the cell membrane. By contrast, no obvious assembly pattern is observed at the adhesion interfaces mediated by mouse DSCAML1 or Drosophila DSCAMs, suggesting the different structural roles and mechanisms of DSCAMs in mediating cell adhesion and neural network formation.

唐氏综合征细胞粘附分子 (DSCAM) 属于免疫球蛋白超家族 (IgSF)，在神经发育中发挥重要作用。它有一个大的胞外域，包括 10 个 Ig 样域和 6 个纤连蛋白 III (FnIII) 域。先前的数据表明，DSCAM 可以通过在细胞之间形成同源二聚体来介导细胞粘附，并有助于神经突或神经元平铺的自我避免，这对于神经网络的形成很重要。然而，DSCAM 在细胞粘附界面的组织和组装尚未完全了解。在这里，我们结合电子显微镜和其他生物物理方法来表征 DSCAM 介导的细胞粘附的结构，并通过电子断层扫描生成 DSCAM 粘附界面的三维视图。结果表明，小鼠 DSCAM 在粘附界面处形成规则的图案。Ig 样结构域对两者都有贡献反式同源相互作用和模式的顺式组装，FnIII结构域对于顺式模式的形成以及与细胞膜的相互作用至关重要。相比之下，在小鼠 DSCAML1 或果蝇DSCAMs 介导的粘附界面上没有观察到明显的组装模式，表明 DSCAMs 在介导细胞粘附和神经网络形成中的不同结构作用和机制。