The crystal structures of the intracellular part of the plexin receptor in the active dimer form, and its complex with a key downstream signalling protein Rap, provide insights into how plexin initiates a signalling cascade involved in axon guidance.
Plexin controls the spatial distribution of synapses by locally inhibiting Rap2 small GTPase activity along the axon, and a Rap2 effector, TNIK, which also plays a key role in inhibiting synapse number.
Zebrafish mutants and human endothelial cell experiments reveal that GIPC family endocytic adaptors bind to the Semaphorin receptor PLEXIND1, a critical regulator of vascular development, to negatively modulate its signaling.
Mice that lack the autism susceptibility gene Semaphorin 5A show excess excitatory synapse formation in dentate granule neurons and also altered social behavior, adding to evidence that a surplus of synapses contributes to the behavioral changes observed in autism spectrum disorders.
Second-order guidance, a novel mechanism by which an initial guidance cue controls expression of a second guidance receptor, is required for precise refinement of axon trajectories during PNS development.