Structure of cell–cell adhesion mediated by the Down syndrome cell adhesion molecule

Abstract

Significance The Down syndrome cell adhesion molecule (DSCAM) is broadly expressed in the nervous system and functions in neural development and network formation by mediating homophilic adhesion between cells. Here we explored the in situ assembly of DSCAM using multiple biochemical and biophysical methods and found that mouse DSCAM is well organized at the adhesion interfaces by forming a regular pattern. Both Ig-like domains and fibronectin III domains contribute to the regular pattern formation but have different roles. By contrast, mouse DSCAML1 or Drosophila DSCAMs do not show similar patterns at the adhesion interfaces. These results suggest that DSCAMs might have different structural roles and mechanisms in regulating neural network formation, which may be associated with corresponding disorders in neural development. 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.