Primary cilia are non-motile protrusions on cells that function as signalling hubs during various developmental processes. The absence or dysfunction of primary cilia leads to a group of neurodevelopment disorders called ciliopathies. Here, Esther Stoeckli and colleagues characterise the role of primary cilium-mediated signalling in commissural axon guidance in mice and chick embryos. First, the authors find that cobblestone mouse embryos with impaired ciliary function phenocopy perturbations of sonic hedgehog (Shh) signalling, a key pathway for axon guidance. Open-book preparations of spinal cords indicate axon guidance defects in cobblestone mouse embryos. Next, to knockdown ciliary genes in a spatiotemporal manner, the authors turn to experiments in chick embryos. They find that Ift88 and Arl13b are required cell-autonomously for commissural axon guidance, and that the primary cilium is necessary for the expression of Hhip, a receptor for the repulsive guidance response to Shh. Furthermore, ex vivo live imaging and in vivo experiments show that smoothened, the primary Shh signalling transducer, must translocate to the cilium for Hhip transcription induction and proper axon turning. Finally, commissural neuron culture experiments suggest that Shh is retrogradely transported from the axonal growth cone back to the primary cilium. Overall, the findings suggest Shh signalling mediated by the primary cilium is required for commissural axon guidance.
