Adhesion-Based Self-Organization in Tissue Patterning

Abstract

Since the proposal of the differential adhesion hypothesis, scientists have been fascinated by how cell adhesion mediates cellular self-organization to form spatial patterns during development. The search for molecular tool kits with homophilic binding specificity resulted in a diverse repertoire of adhesion molecules. Recent understanding of the dominant role of cortical tension over adhesion binding redirects the focus of differential adhesion studies to the signaling function of adhesion proteins to regulate actomyosin contractility. The broader framework of differential interfacial tension encompasses both adhesion and nonadhesion molecules, sharing the common function of modulating interfacial tension during cell sorting to generate diverse tissue patterns. Robust adhesion-based patterning requires close coordination between morphogen signaling, cell fate decisions, and changes in adhesion. Current advances in bridging theoretical and experimental approaches present exciting opportunities to understand molecular, cellular, and tissue dynamics during adhesion-based tissue patterning across multiple time and length scales.

Keywords: cell adhesion; cell sorting; developmental biology; interfacial tension; tissue patterning.

Figure 1:. From differential adhesion to differential interfacial tension.

(A) Three distinct ways for cadherins to modulate interfacial tension: (1) cadherin binding in trans increase adhesion tension, (2) cadherin intracellular domains anchor to actomyosin cytoskeleton through catenins to stabilize cadherin binding in trans. (3) the intracellular domain of cadherin signals to change cytoskeleton structure and lower actomyosin contractility. (B) adhesion tension (orange arrows) acts to lower interfacial tension and stabilize the contact, while cortical tension (green arrows) acts to increase interfacial tension and shrink the contact. When interfacial tension increases, contact angle (θ) decreases and contact area shrinks. When interfacial tension decreases, contact angle (θ) increases and contact area expands.

Figure 2:. Patterns mediated by adhesion-based sorting in a two-component system.

(Left) Schematic identifying interfacial tension at each possible cell-cell interface in a mixture of two different cell types labeled “A” and “B”. Example cell shapes are shown for cases where adhesions facilitate either a homotypic or heterotypic preference. (Right) The types of patterns that have been demonstrated to arise by differential adhesion, organized by the relative interfacial tension at homotypic and heterotypic interfaces.

Figure 3:. Molecular toolkits to modulate interfacial tension.

Cadherin superfamily genes form homophilic in trans to modulate stability of homotypic contacts. Among them, classical cadherins can signal to actomyosin cytoskeleton to reduce interfacial tension, while clustered protocadherins can signal to increase interfacial tension at homotypic contact. Nectins form stronger heterophilic adhesion than homophilic adhesion, and preferentially stabilize heterotypic contact. Upon binding of Eph receptors and ephrin ligands, they signal to actomyosin cytoskeleton to increase interfacial tension and shrink the heterotypic contact.