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REVIEW

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

Amparo Palmer1 and Ru¨diger Klein2

Max-Planck Institute of Neurobiology, Department of Molecular Neurobiology, D-82152 Martinsried, Germany

Cell-to-cell communication during development and gration of neighboring cells, and the production of extra- plasticity is controlled to a large extent by signaling cellular matrix proteins by differentiating cells. Through events downstream of receptor tyrosine kinases (RTKs). binding to their cognate protein ligands, receptor tyro- Most RTKs bind soluble ligands, which are often pro- sine kinases are sensors of such environmental changes duced at a distance from the RTK-expressing cells, and and transmit information to the inside of the cell. Of all therefore these interactions typically mediate long-range the RTKs in the human genome, Eph receptors consti- communication. Eph receptors (or Ephs), instead, bind tute the largest subfamily, which probably arose through membrane-bound ephrin ligands expressed by neighbor- rather recent gene duplications. Its 13 members (in ing cells and mediate short-range cell-to-cell communi- mammals) are subdivided based on sequence similarity cation. The influence of ephrin–Eph interaction on cell and ligand-binding characteristics into an A-subclass behavior depends on the cell type, but can in most cases (EphA1–EphA8) and a B-subclass (EphB1–EphB4, EphB6) be interpreted as repulsion of neighboring cells or of cel- with partially overlapping functions (for reviews, see lular processes, such as the neuronal growth cone. How- Wilkinson 2001; Kullander and Klein 2002). Their li- ever, in some cases ephrin–Eph activation can have the gands, the ephrins, are also subdivided into an A-sub- opposite effect, that is, increased adhesion/attraction. class (ephrinA1–ephrinA5), which are tethered to the One subclass of ephrins, the ephrinB ligands, are trans- exoplasmic leaflet of the cell membrane by a glyco- membrane proteins with intrinsic (so-called reverse) sig- sylphosphatidylinositol (GPI) anchor, and the B-subclass naling properties (for review, see Kullander and Klein (ephrinB1–ephrinB3), which contain transmembrane and 2002). This complicates the interpretation of functional cytoplasmic regions. EphrinA ligands typically bind to assays and genetic phenotypes, because manipulations EphA receptors, and ephrinB ligands bind to EphB recep- intended to eliminate forward receptor function often tors. The EphA4 receptor has a broader ligand-binding have consequences for reverse signaling as well. This spectrum, as it can bind most ephrinA, as well as eph- review summarizes the diverse biological roles of eph- rinB2 and ephrinB3, but not ephrinB1, ligands. rins and Ephs in embryonic development, including pat- The ephrin–Eph system is unique among the RTK terning and morphogenetic processes of the nervous and family mainly for two reasons: First, ephrinB ligands vascular systems, and in the adult, such as synaptic plas- (and perhaps also ephrinAs) not only induce signaling ticity. We further touch upon more recent observations downstream of the Eph receptors (forward signaling), but on ephrin functions in , re- also signal themselves into the cell that expresses generation, and tumorigenesis. Our focus is on, but is them—referred to as reverse signaling (see below). Sec- not restricted to, recent findings using genetically ame- ond, functional ephrin–Eph signaling might require the nable systems. generation of a higher-order complex, and the quality of the signaling output exerted by higher-order clusters seems to be different from the one exerted by a receptor General features of ephrins and Ephs dimer (Stein et al. 1998). Structural data showed that Eph Durin