Upon reaching its target, an axon differentiates to form synaptic connections. Remarkably, recent studies have revealed that proteins initially identified as axon guidance cues are re-emerging as regulators of synaptic plasticity in the adult brain. Canonical axon guidance proteins such as semaphorins, ephrins, and slits, and the prototypical myelin-associated inhibitors of axon regeneration, MAG, Nogo, and OMgp, have been found to influence circuit remodeling and synaptic plasticity in the mature nervous system (Mironova and Giger, 2013). Following a study by Horn et al (2013), the netrin receptor DCC now joins this list.

Mechanisms that direct neural development have long been suggested to regulate plasticity in the mature brain. Cajal’s (1911) proposal that chemotropism might direct axon extension in the embryo included a hypothesized attractant for commissural axons secreted by floor plate cells in the embryonic spinal cord. In a stunning act of prescience, Cajal (1911) suggested that his putative chemoattractant might also influence synaptic plasticity and learning and memory: ‘The ability of neurons to grow in an adult and their power to create new associations can explain learning.’ He speculated that ‘the mechanisms are probably chemotactile like the ones we observed during histogenesis of the spinal cord’ .

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