D-Eph-ective endocytosis disrupts topographic mapping.

Since the discovery of the ephrin/Eph family of axon guidance molecules in the early ‘90s, research has often uncovered rather surprising aspects of their biology (Pasquale, 2008). A paper in this issue of The EMBO Journal provides further, novel insights into ephrin/Eph function. Here, the Park lab demonstrates the importance of Eph/ephrin endocytosis for retinotectal mapping, an interesting—though not unexpected—finding in itself. However, the surprise comes with their demonstration that endocytosis of the Eph/ephrin complex into neurons of the target structure, rather than into the retinal axons themselves, is of critical importance. Endocytosis has been considered to be important for Eph family function for some time now to resolve the following paradox: the high-affinity interaction between Eph and ephrin-expressing cells is normally repellent, but both the Ephs and the ephrins are membrane-bound. This implies that the interaction between Ephs and ephrins must somehow be ‘broken’ to enable a separation of the cells bearing these two membrane proteins. In fact, recent in vitro work has shown that cell contact is terminated by induced shedding of ephrins (Hattori et al, 2000; Janes et al, 2005) or by endocytosis of the entire Eph/ephrin complex (Marston et al, 2003; Zimmer et al, 2003; for a recent review, see Pitulescu and Adams, 2010). In vivo experiments from the Park lab now provide intriguing new insights into the role of endocytosis in the development of the retinocollicular map in mice. In this model system, topographic mapping of retinal axons to their correct termination zones in the superior colliculus (SC) is controlled by multiple gradients of Ephs and ephrins expressed in both the retina and the SC (Huberman et al, 2008). The Park lab has investigated the targeting of nasal RGC axons to the posterior SC, which depends predominantly on the repulsion of nasal axons expressing ephrinAs from the anterior SC expressing numerous different EphAs (Rashid et al, 2005; Lim et al, 2008) (Figure 1A). Initially the authors found that overexpression of EphA8 in the anterior SC (via bacterial artificial chromosomes) pushes