EphA (green) and ephrinA (red) membrane localization does not overlap.


Axonal pathfinding in motor neurons depends on surrounding guidance cues, including the membrane-bound ephrinA ligands, which repel growth cones that express EphA receptors. But many of those same growth cones also contain their own ephrinA. Now, Till Marquardt, Ryuichi Shirasaki, Samuel Pfaff, and colleagues (Salk Institute, La Jolla, CA) show how EphA ignores self-ephrinA during growth cone guidance.The authors find that ephrinA ligands that are on the same cell as a EphA receptor do not interfere with that receptor's ability to sense ligands on other cells. The interference is avoided by segregating receptor and ligand to different submembrane domains. EphrinA ligands, which are GPI-linked, colocalized with a lipid raft marker. EphA receptors, on the other hand, were found in nearby but distinct (presumably nonraft) domains. Forced mixing of the two, by expressing a transmembrane version of the ligand, made neurons blind to ephrinA ligands outside the cell.

When external EphA receptors bind to ephrinAs, the latter are also known to signal back into their own cell, but they elicit growth cone expansion rather than collapse. As with EphA receptors, this effect depended on the separation of EphA and ephrinA. Both EphrinA and EphA can thus act as guidance receptors on the same growth cone, with opposite results.

Decreased sensitivity to external ligand or receptors might be achieved naturally by regulated colocalization. The resulting desensitization might allow, for example, several axons that express both EphA and ephrinA to grow out as a bundle without repelling each other.


Marquardt, T., et al.