Boc Acts via Numb as a Shh-Dependent Endocytic Platform for Ptch1 Internalization and Shh-Mediated Axon Guidance

During development, Shh attracts commissural axons toward the floor plate through a non-canonical, transcription-independent signaling pathway that requires the receptor Boc. Here, we find that Shh induces Boc internalization into early endosomes and that endocytosis is required for Shh-mediated growth-cone turning. Numb, an endocytic adaptor, binds to Boc and is required for Boc internalization, Shh-mediated growth-cone turning in vitro, and commissural axon guidance in vivo. Similar to Boc, Ptch1 is also internalized by Shh in a Numb-dependent manner; however, the binding of Shh to Ptch1 alone is not sufficient to induce Ptch1 internalization nor growth-cone turning. Therefore, the binding of Shh to Boc is required for Ptch1 internalization and growth-cone turning. Our data support a model where Boc endocytosis via Numb is required for Ptch1 internalization and Shh signaling in axon guidance. Thus, Boc acts as a Shh-dependent endocytic platform gating Ptch1 internalization and Shh signaling. [Display omitted] •Sonic hedgehog (Shh) induces endocytosis of Boc and Ptch1 into Rab5 endosomes•The endocytic adaptor Numb binds to Boc and is required for Boc endocytosis•Numb is required for Shh-mediated axon attraction in vitro and axon guidance in vivo•Binding of Shh to Boc is required for Ptch1 endocytosis and Shh axon attraction Ferent et al. elucidate how the Shh receptor Boc works together with Ptch1 to transduce the Shh signal in axon guidance. They demonstrate that Numb-mediated internalization of Boc is required for Ptch1 internalization, activation of signaling, and Shh-mediated axon guidance.