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Signaling Switch of the Axon Guidance Receptor Robo3 during Vertebrate Evolution

Abstract : 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.
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Pavol Zelina, Heike Blockus, Yvrick Zagar, Amélie Péres, François Friocourt, et al.. Signaling Switch of the Axon Guidance Receptor Robo3 during Vertebrate Evolution. Neuron, Elsevier, 2014, 84 (6), pp.1258-1272. ⟨10.1016/j.neuron.2014.11.004⟩. ⟨hal-01102724⟩

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