Axon guidance relies on growth cones detecting molecular cues to direct axonal attraction and repulsion and, hence, control neural circuit formation. This process involves second messengers like cyclic AMP (cAMP), which compartmentalise into distinct cellular domains to activate downstream effectors, like focal adhesion kinase (FAK), a key regulator of point contacts (PCs). PCs link extracellular matrix proteins to the actin cytoskeleton through various adaptor and signalling proteins, facilitating efficient growth cone migration. Here (Bécret et al., 2025), Xavier Nicol and colleagues show that PC-restricted cAMP signalling regulates ephrin-A5-mediated axon guidance. The authors electroporate mouse retinal explants with a PC-targeted cAMP sponge to prevent changes in cAMP levels within PCs. They show that PC-restricted cAMP signalling is essential for axon retraction, PC turnover, PC density and the regulation of FAK phosphorylation, a modification critical for axon retraction. Furthermore, buffering cAMP in lipid rafts does not affect FAK phosphorylation, highlighting the specificity of PC-localised signalling pathways. Finally, disrupting PC-restricted cAMP signalling in vivo in the brain impairs the terminal arborisation of retinal axonal projections. Taken together, these findings emphasise the crucial role of subcellular second messenger compartmentation in axon guidance and advance our understanding of how growth cones decode complex guidance cues to establish precise neural circuits.
