A central role for Numb/Nbl in multiple Shh-mediated axon repulsion processes

Sonic hedgehog (Shh) is an axon guidance molecule that can act as either a chemorepellent or a chemoattractant, depending on the neuron type and their developmental stage. In the developing spinal cord, Shh initially attracts commissural axons to the floor plate and later repels them after they cross the midline. In the developing visual system, Shh repels ipsilateral retinal ganglion cell (iRGC) axons at the optic chiasm. Although Shh requires the endocytic adaptor Numb for attraction of spinal commissural axons, the molecular mechanisms underlying Shh dual function in attraction and repulsion are still unclear. In this study, we show that Numb is essential for two Shh-mediated repulsion processes: iRGC axon repulsion at the optic chiasm and antero-posterior commissural axon repulsion in the spinal cord. Therefore, Numb is required for Shh-mediated attraction and repulsion. These results position Numb as a central player in the non-canonical Shh signaling pathway mediating axon repulsion.