Numb positively regulates hedgehog signaling at the ciliary pocket
Hedgehog (Hh) signaling depends on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identified 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 egress from the cilium, a key step in Hh signaling activation. Loss of Numb impairs Sonic hedgehog (Shh)-induced Ptch1 egress from the cilium, reducing Hh signaling. Loss of Numb in spinal neural progenitors reduces Shh-induced differentiation into cell fates dependent on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs granule cell precursor proliferation, an Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels upon Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.
