Bidirectional Eph–ephrin signaling during axon guidance

Ephrins are cell-surface tethered guidance cues that bind to Eph receptor tyrosine kinases in trans on opposing cells. In the developing nervous system, the Eph–ephrin signaling system controls a large variety of cellular responses including contact-mediated attraction or repulsion, adhesion or de-adhesion, and migration. Eph–ephrin signaling can be bidirectional, and is subject to modulation by ectodomain cleavage of ephrins and by Eph–ephrin endocytosis. Recent work has highlighted the importance of higher-order clustering of functional Eph–ephrin complexes and the requirement for Rho GTPases as signal transducers. Co-expression of Ephs and ephrins within the same cellular membrane can result in Eph–ephrin cis interaction or in lateral segregation into distinct domains from where they signal opposing effects on the axon.