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A switch in the response of commissural axons to the repellent Slit is critical for ensuring that they cross the ventral midline only once. However, the underlying mechanisms remain to be elucidated. We found that both endocytosis and recycling of Robo1 receptor are crucial for modulating Slit sensitivity in vertebrate commissural axons. Robo1 endocytosis and its recycling back to the cell-surface maintained the stability of axonal Robo1 during Slit stimulation. We identified Arf6 guanosine triphosphatase and its activators, cytohesins, as previously unknown components in Slit-Robo1 signalling in vertebrate commissural neurons. Slit-Robo1 signalling activated Arf6. The Arf6-deficient mice exhibited marked defects in commissural axon midline-crossing. Our data showed that a Robo1 endocytosis-triggered and Arf6-mediated positive-feedback strengthens Slit response in commissural axons upon their midline crossing. Furthermore, cytohesin-Arf6 pathways modulated this self-enhancement of Slit response before and after midline crossing, resulting in a switch that reinforced robust regulation of axon midline crossing. Our study provides insights into endocytic trafficking-mediated mechanisms for spatiotemporally controlled axonal responses and uncovers new players in the midline switch in Slit responsiveness of commissural axons.

A critical role of Arf6 in the response of commissural axons to Slit