Subcellular second messenger networks drive distinct repellent-induced axon behaviors

Second messengers, including cAMP, cGMP and Ca 2+ are often placed in an integrating position to combine the extracellular cues that orient growing axons in the developing brain. This view suggests that axon repellents share the same set of cellular messenger signals and that axon attractants evoke opposite cAMP, cGMP and Ca 2+ changes. Investigating the confinement of these second messengers in cellular nanodomains, we instead demonstrate that two repellent cues, ephrin-A5 and Slit1, induce spatially segregated signals. These guidance molecules activate subcellular-specific second messenger crosstalk, each signaling network controlling distinct axonal morphology changes in vitro and pathfinding decisions in vivo. Signals from extracellular cues orienting growing axons are thought to be integrated by second messenger molecules. Here, Baudet et al. instead demonstrate that distinct axon guidance cues induce cAMP, cGMP and Ca 2+ signals restricted to separate cellular nanodomains.