Point contact-restricted cAMP signaling controls ephrin-A5-induced axon repulsion

Signal transduction downstream of axon guidance molecules is essential for steering developing axons. Second messengers including cAMP are key molecules shared by a multitude of signaling pathways and are required for a wide range of cellular processes including axon pathfinding. Yet, how these signaling molecules achieve specificity for each of their downstream pathways remains elusive. Subcellular compartmentation has emerged as a flexible strategy to reach such a specificity. Here, we show that point contact-restricted cAMP signals control ephrin-A5-evoked axon repulsion in vitro by modulating focal adhesion kinase (FAK; also known as PTK2) phosphorylation and the assembly and disassembly rate of point contacts. Consistent with this, preventing point contact-specific cAMP signals in developing retinal ganglion cells in vivo alters the refinement of their terminal axonal arbor in the brain. Altogether, our study identifies point contacts as a compartment containing a local cAMP signal required for ephrin-A5-dependent axon guidance and highlights the crucial role of such subcellularly restricted second messenger signals in the wiring of neuronal circuits.