Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function

Cell-to-cell communication during development and plasticity is controlled to a large extent by signaling events downstream of receptor tyrosine kinases (RTKs). Most RTKs bind soluble ligands, which are often produced at a distance from the RTK-expressing cells, and therefore these interactions typically mediate long-range communication. Eph receptors (or Ephs), instead, bind membrane-bound ephrin ligands expressed by neighboring cells and mediate short-range cell-to-cell communication. The influence of ephrin–Eph interaction on cell behavior depends on the cell type, but can in most cases be interpreted as repulsion of neighboring cells or of cellular processes, such as the neuronal growth cone. However, in some cases ephrin–Eph activation can have the opposite effect, that is, increased adhesion/attraction. One subclass of ephrins, the ephrinB ligands, are transmembrane proteins with intrinsic (so-called reverse) signaling properties (for review, see Kullander and Klein 2002). This complicates the interpretation of functional assays and genetic phenotypes, because manipulations intended to eliminate forward receptor function often have consequences for reverse signaling as well. This review summarizes the diverse biological roles of ephrins and Ephs in embryonic development, including patterning and morphogenetic processes of the nervous and vascular systems, and in the adult, such as synaptic plasticity. We further touch upon more recent observations on ephrin functions in neurogenesis, nervous system regeneration, and tumorigenesis. Our focus is on, but is not restricted to, recent findings using genetically amenable systems.