Tuning Collective Cell Migration by Cell-Cell Junction Regulation

Abstract

Collective cell migration critically depends on cell-cell interactions coupled to a dynamic actin cytoskeleton. Important cell-cell adhesion receptor systems implicated in controlling collective movements include cadherins, immunoglobulin superfamily members (L1CAM, NCAM, ALCAM), Ephrin/Eph receptors, Slit/Robo, connexins and integrins, and an adaptive array of intracellular adapter and signaling proteins. Depending on molecular composition and signaling context, cell-cell junctions adapt their shape and stability, and this gradual junction plasticity enables different types of collective cell movements such as epithelial sheet and cluster migration, branching morphogenesis and sprouting, collective network migration, as well as coordinated individual-cell migration and streaming. Thereby, plasticity of cell-cell junction composition and turnover defines the type of collective movements in epithelial, mesenchymal, neuronal, and immune cells, and defines migration coordination, anchorage, and cell dissociation. We here review cell-cell adhesion systems and their functions in different types of collective cell migration as key regulators of collective plasticity.

Figure 1.

Composition of cell–cell adhesions and related types of collective cell behaviors. Morphological organization of cell–cell interactions, related collective cell dynamics (upper panels), and their respective stability (cyan), molecular composition (blue), and multicellular function outcomes (pink; bottom panels). Different examples show variable levels of cell adhesion (blue dots) and cell movement (arrows, direction of migration). (A) Myofiber network. (B) Gut epithelium renewing. (C) Branching morphogenesis. (D) Drosophila border cells. (E) Neural crest. (F) Leukocytes. IgCAMs, immunoglobulin-like cell-adhesion molecules; Robo, roundabout receptors.

Figure 2.

EMT spectrum tuning the modes of collective and individual-cell migration. (A) Resting epithelial tissue. (B) Partial EMT in the leading cells can retain cell–cell junctions and promote epithelial sheet migration. (C) Cluster migration after group detachment from the main tissue. Migrating clusters can maintain apicobasal polarity, strong and stable cell adhesion mediated mainly by E-cadherin, or undergo further mesenchymal plasticity. (D, E) Full EMT leads to reduced cell adhesion, associated with down-modulated E-cadherin and increased N-cadherin expression, followed by loss of apicobasal polarity, acquisition of front–back polarity and increased individual motility. Transient junctions allow for collective network migration (D), and complete resolution of cell–cell junctions favors individualization and single-cell migration (E). EMT, epithelial-to-mesenchymal transition; IgCAMs, immunoglobulin-like cell-adhesion molecules.