Expanding ligand-receptor interaction networks for axon guidance: Structural insights into signal crosstalk and...

Guidance of nascent axons to their targets is mediated by attractive and repulsive cues that activate receptors on the axonal growth cone. The number of ligand-receptor interactions implicated in axon pathfinding is still expanding, and large-scale cell-surface and extracellular protein interactome studies have revealed extensive crosstalk between signaling axes once thought to act independently. This raises the question how the apparent promiscuity of molecular interactions is compatible with specific signaling outcomes and effects on growth cone steering. Structural studies have provided insights into the modularity of binding interactions and shown the capacity of receptors to engage multiple ligands. Here, we review recent findings about the complexity of ligand-receptor interaction networks for axon guidance, and how structures of ligand-receptor complexes reveal mechanisms that may specify signaling output.