Formation and maintenance of distinctive cell patterns by coexpression of membrane-bound ligands and their receptors.

Abstract

We show that graded or checkerboard-like cell patterns, and segmental domains along a body axis, can be generated by cell behaviors involving differences in intercellular repulsion. A membrane-bound signal transduction system mediating contact-dependent cell interactions includes membrane-bound ligands (ephrins) and their receptors with tyrosine-kinase activity (Eph proteins). These molecules mediate both repulsive and attractive interactions under bilateral threshold control, i.e., cells expressing the receptors adhere to a surface bearing a critical density of ligand reciprocal to the density of receptor but are repelled by a surface with other densities of ligand (Honda [1998] J. Theor. Biol. 192:235-246). We extend this model. General membrane-bound ligands (not always ephrins) and their receptors are presumably coexpressed in a single cell under bilateral threshold control. Computer simulations of cell pattern formation showed that when coexpression of the ligand and receptor is reciprocal, the cells self-organize into a pattern of segmental domains or a graded cell arrangement along the body axis. The latter process interprets positional information in terms of protein molecules. When coexpression of the two species of molecules is not always reciprocal, the cells generate various patterns including checkerboard and kagome (star) patterns. The case of separate expression of ligands and receptors in different cells is also examined. The mechanism of differences in cell repulsion is compared with the differential cell adhesion hypothesis, which has been used to explain cell sorting.