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.
Montreal Clinical Research Institute (IRCM), 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
Neuron. 2019 Jun 19;102(6):1157-1171.e5. doi: 10.1016/j.neuron.2019.04.003. Epub 2019 May 1.
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.
在发育过程中，Shh 通过一种非经典的、不依赖于转录的信号通路吸引连合轴突向基板移动，该通路需要受体 Boc。在这里，我们发现 Shh 诱导 Boc 内陷到早期内体中，内吞作用对于 Shh 介导的生长锥转向是必需的。内吞作用衔接蛋白 Numb 与 Boc 结合，并参与 Boc 内陷、Shh 介导的体外生长锥转向和连合轴突的体内导向。与 Boc 类似，Ptch1 也被 Shh 以 Numb 依赖的方式内陷；然而，Shh 与 Ptch1 的结合本身不足以诱导 Ptch1 内陷和生长锥转向。因此，Shh 与 Boc 的结合对于 Ptch1 的内陷和生长锥转向是必需的。我们的数据支持这样一种模型，即通过 Numb 的 Boc 内吞作用对于 Ptch1 的内陷和 Shh 信号在轴突导向中的作用是必需的。因此，Boc 作为一个 Shh 依赖性的内吞平台，控制着 Ptch1 的内陷和 Shh 信号。
