1. Numb positively regulates Hedgehog signaling at the ciliary pocket
- Author
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Liu, Xiaoliang, Yam, Patricia T, Schlienger, Sabrina, Cai, Eva, Zhang, Jingyi, Chen, Wei-Ju, Torres Gutierrez, Oscar, Jimenez Amilburu, Vanesa, Ramamurthy, Vasanth, Ting, Alice Y, Branon, Tess C, Cayouette, Michel, Gen, Risako, Marks, Tessa, Kong, Jennifer H, Charron, Frédéric, and Ge, Xuecai
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Stem Cell Research ,1.1 Normal biological development and functioning ,Hedgehog Proteins ,Cilia ,Animals ,Signal Transduction ,Patched-1 Receptor ,Mice ,Nerve Tissue Proteins ,Cerebellum ,Membrane Proteins ,Humans ,Endocytosis ,Cell Differentiation ,Cell Proliferation ,Neural Stem Cells ,Mice ,Knockout - Abstract
Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identify Numb as a ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impedes Sonic hedgehog (Shh)-induced Ptch1 exit from the cilium, resulting in reduced Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into cell fates reliant on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.
- Published
- 2024