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Development of neuronal circuits is controlled by evolutionarily conserved axon guidance molecules, including Slits, the repulsive ligands for roundabout (Robo) receptors, and Netrin-1, which mediates attraction through the DCC receptor. We discovered that the Robo3 receptor fundamentally changed its mechanism of action during mammalian evolution. Unlike other Robo receptors, mammalian Robo3 is not a high-affinity receptor for Slits because of specific substitutions in the first immunoglobulin domain. Instead, Netrin-1 selectively triggers phosphorylation of mammalian Robo3 via Src kinases. Robo3 does not bind Netrin-1 directly but interacts with DCC. Netrin-1 fails to attract pontine neurons lacking Robo3, and attraction can be restored in Robo3−/− mice by expression of mammalian, but not nonmammalian, Robo3. We propose that Robo3 evolution was key to sculpting the mammalian brain by converting a receptor for Slit repulsion into one that both silences Slit repulsion and potentiates Netrin attraction.
•A role for Robo3 is found in the evolution of vertebrate brain connectivity•Positive selection confers chemoattractive signaling properties to mammalian Robo3•Slits do not bind with high affinity to mammalian Robo3 receptors•Netrin-1 activates mammalian Robo3 through DCC and Src kinases
Axon guidance mechanisms at the midline are thought to be highly conserved in evolution. However, Zelina et al. show here that mammalian Robo3 receptors have unique signaling properties and function. They do not bind Slits and mediate Netrin-1 attraction. This might have contributed to the emergence of mammalian-specific commissural circuits.