Asymmetry at cell-cell interfaces direct cell sorting, boundary formation, and tissue morphogenesis

Abstract

During development, cells of seemingly homogenous character sort themselves out into distinct compartments in order to generate cell types with specialized features that support tissue morphogenesis and function. This process is often driven by receptors at the cell membrane that probe the extracellular microenvironment for specific ligands and alter downstream signaling pathways impacting transcription, cytoskeletal organization, and cell adhesion to regulate cell sorting and subsequent boundary formation. This review will focus on two of these receptor families, Eph and Notch, both of which are intrinsically non-adhesive and are activated by a unique set of ligands that are asymmetrically distributed from their receptor on neighboring cells. Understanding the requirement of asymmetric ligand-receptor signaling at the membrane under homeostatic conditions gives insight into how misregulation of these pathways contributes to boundary disruption in diseases like cancer.

EphA2/Ephrin-A1 Mediate Corneal Epithelial Cell Compartmentalization via ADAM10 Regulation of EGFR Signaling

“…There is a sharp transition between basal cells of the limbal epithelium and the more differentiated basal cells of the corneal epithelium, which is referred to as the limbal–corneal epithelial junction. 1 , 4 Given the role of Eph/ephrins in cell segregation and boundary formation 9 and our previous data showing a role for EphA2 and ephrin-A1 in corneal epithelial cell migration, 7 we examined the expression patterns of this receptor–ligand system in various zones (i.e., limbus, limbal–corneal junction, central cornea) of the human cornea using frozen tissue sections ( Fig. 1 A).…”

“…Juxtacrine signaling through Eph receptors and ephrin ligands regulate tissue patterning and boundary formation throughout development and continue to be important for homeostasis of adult tissues. 9 What constitutes and controls the boundary between limbal and corneal epithelia has been under intense scrutiny for some time. 1 , 4 Surprisingly, the Eph/ephrin signaling pathway has not been studied extensively in this context.…”

“…Signaling through Eph receptors and their ephrin ligands participate in a variety of physiologic activities such as differentiation, migration, and tissue boundary formation. 5 – 9 For example, ephrin-A family ligands have been shown to promote keratinocyte differentiation and inhibit migration largely by acting on EphA2. 7 , 10 , 11 Accordingly, EphA2 loss is associated with increased tumor growth in the skin of mice.…”

EphA2 Transmembrane Domain Is Uniquely Required for Keratinocyte Migration by Regulating Ephrin-A1 Levels

“…Although cell migration is required for normal tissue patterning and wound healing, cancer cells use similar mechanisms to promote tumor invasion. Redundant molecular mechanisms control cell migration, including those engaged by Eph/ephrins (Ventrella et al, 2017). Tumors that express high levels of EphA2 are often accompanied by loss of ephrin-A1.…”

Gulp1 controls Eph/ephrin trogocytosis and is important for cell rearrangements during development

“…This partial eating behavior is required to remove the adhesive receptor–ligand complex that forms at the interface of the two opposing cells (Riccomagno and Kolodkin, 2015; Wen and Winklbauer, 2017). Ephrin receptor (Eph) tyrosine kinases and their membrane-bound ephrin ligands are prominent inducers of contact repulsion during embryonic development (Batlle and Wilkinson, 2012; Ventrella et al, 2017). Both receptors and ligands comprise two subfamilies: EphAs that preferentially bind glycosylphosphatidylinositol-anchored ephrinAs and EphBs that prefer binding transmembrane ephrinBs (Kania and Klein, 2016).…”