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Neuron. 2019 Apr 24. pii: S0896-6273(19)30338-1. doi: 10.1016/j.neuron.2019.04.003. [Epub ahead of print]

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

Author information

1
Montreal Clinical Research Institute (IRCM), 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Neuroscience, University of Montreal, Montreal, QC H3T 1J4, Canada.
2
Montreal Clinical Research Institute (IRCM), 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
3
Montreal Clinical Research Institute (IRCM), 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada.
4
Montreal Clinical Research Institute (IRCM), 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Biology, McGill University, Montreal, QC H3A 0G4, Canada. Electronic address: frederic.charron@ircm.qc.ca.

Abstract

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.

KEYWORDS:

Boc; Numb; Patched1; axon guidance; commissural neurons; endocytosis; sonic hedgehog

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