Eph receptors and ephrins: regulators of guidance and assembly

Recent advances have started to elucidate the developmental functions and biochemistry of Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins. Interactions between these molecules are promiscuous, but they largely fall into two groups: EphA receptors bind to GPI-anchored ephrin-A ligands, while EphB receptors bind to ephrin-B proteins that have a transmembrane and cytoplasmic domain. Remarkably, ephrin-B proteins transduce signals, such that bidirectional signaling can occur upon interaction with Eph receptor. In many tissues, specific Eph receptors and ephrins have complementary domains, whereas other family members may overlap in their expression. An important role of Eph receptors and ephrins is to mediate cell-contact-dependent repulsion. Complementary and overlapping gradients of expression underlie establishment of a topographic map of neuronal projections in the retinotectal system. Eph receptors and ephrins also act at boundaries to channel neuronal growth cones along specific pathways, restrict the migration of neural crest cells, and via bidirectional signaling prevent intermingling between hindbrain segments. Intriguingly, Eph receptors and ephrins can also trigger an adhesive response of endothelial cells and are required for the remodeling of blood vessels. Biochemical studies suggest that the extent of multimerization of Eph receptors modulates the cellular response and that the actin cytoskeleton is one major target of the intracellular pathways activated by Eph receptors. Eph receptors and ephrins have thus emerged as key regulators of the repulsion and adhesion of cells that underlie the establishment, maintenance, and remodeling of patterns of cellular organization.