PERSPECTIVE Signaling fromWithin: Endocytic Trafficking of the Robo Receptor Is Required for Midline Axon Repulsion

Proper guidance and wiring of axons during development is essential for the normal function of the nervous system. Despite the identification, over the last 20 years or so, of many axon guidance cues and their cognate receptors, we still do not fully understand how their intracellu-lar signal transduction is elicited. Current models often depict that ligand binding to its recep-tor at the surface of the growth cone leads to the activation of the receptor, recruitment, and/or activation of signaling molecules near the cytoplasmic tail of the receptor, resulting in local sig-naling emanating from the subcellular compartment where the receptor was located upon binding of its ligand (Fig 1a). An article by Chance and Bashaw, published in this issue of PLOS Genetics, uses complementary in vivo and in vitro experiments to challenge this view and show that endocytosis of the Roundabout (Robo) receptor is a key component of receptor activation and precedes the recruitment of its effectors to the receptor cytoplasmic domain [1]. In both invertebrates and vertebrates, Robo receptors comprise a family of axon guidance receptors that mediate repulsion in response to their Slit ligands. In the Drosophila embryonic ventral nerve cord, Slit is expressed by midline glia, which creates a repulsive zone for growth cones expressing Robo at their surface. In robomutants, axons that normally do not cross th