Numb positively regulates Hedgehog signaling at the ciliary pocket.
Hedgehog Proteins
/ metabolism
Cilia
/ metabolism
Animals
Signal Transduction
Patched-1 Receptor
/ metabolism
Mice
Nerve Tissue Proteins
/ metabolism
Cerebellum
/ metabolism
Membrane Proteins
/ metabolism
Humans
Endocytosis
Cell Differentiation
Cell Proliferation
Neural Stem Cells
/ metabolism
Mice, Knockout
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 Apr 2024
25 Apr 2024
Historique:
received:
16
07
2022
accepted:
25
03
2024
medline:
26
4
2024
pubmed:
26
4
2024
entrez:
25
4
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38664376
doi: 10.1038/s41467-024-47244-1
pii: 10.1038/s41467-024-47244-1
doi:
Substances chimiques
Hedgehog Proteins
0
Patched-1 Receptor
0
Numb protein, mouse
0
Nerve Tissue Proteins
0
Membrane Proteins
0
Ptch1 protein, mouse
0
Shh protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3365Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : GM143276
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : CA235749
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : CA274595
Organisme : National Science Foundation (NSF)
ID : IOS-2143711
Informations de copyright
© 2024. The Author(s).
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