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Numb positively regulates Hedgehog signaling at the ciliary pocket.

Xiaoliang LiuPatricia T YamSabrina SchliengerEva CaiJingyi ZhangWei-Ju ChenOscar Torres GutierrezVanesa Jimenez AmilburuVasanth RamamurthyAlice Y TingTess C BranonMichel CayouetteRisako GenTessa MarksJennifer H KongFrédéric CharronXuecai Ge
Published in: Nature communications (2024)
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.
Keyphrases
  • single cell
  • cell therapy
  • signaling pathway
  • gene expression
  • mass spectrometry
  • high glucose
  • oxidative stress
  • spinal cord injury
  • bone marrow
  • dna methylation
  • drug induced