Numb positively regulates Hedgehog signaling at the ciliary pocket

Xiaoliang Liu, Patricia T. Yam, Sabrina Schlienger, Eva Cai, Jingyi Zhang, Wei-Ju Chen, Oscar Torres Gutierrez, Vanesa Jimenez Amilburu, Vasanth Ramamurthy, Alice Y. Ting, Tess C. Branon, Michel Cayouette, Risako Gen, Tessa Marks, Jennifer H. Kong, Frédéric Charron () and Xuecai Ge ()
Additional contact information
Xiaoliang Liu: University of California, Merced
Patricia T. Yam: Montreal Clinical Research Institute (IRCM)
Sabrina Schlienger: Montreal Clinical Research Institute (IRCM)
Eva Cai: University of California, Merced
Jingyi Zhang: University of California, Merced
Wei-Ju Chen: Montreal Clinical Research Institute (IRCM)
Oscar Torres Gutierrez: University of California, Merced
Vanesa Jimenez Amilburu: Montreal Clinical Research Institute (IRCM)
Vasanth Ramamurthy: Montreal Clinical Research Institute (IRCM)
Alice Y. Ting: Stanford University
Tess C. Branon: Stanford University
Michel Cayouette: Montreal Clinical Research Institute (IRCM)
Risako Gen: University of Washington
Tessa Marks: University of Washington
Jennifer H. Kong: University of Washington
Frédéric Charron: Montreal Clinical Research Institute (IRCM)
Xuecai Ge: University of California, Merced

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47244-1

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