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Numb positively regulates Hedgehog signaling at the ciliary pocket

Author

Listed:
  • Xiaoliang Liu

    (University of California, Merced)

  • Patricia T. Yam

    (Montreal Clinical Research Institute (IRCM))

  • Sabrina Schlienger

    (Montreal Clinical Research Institute (IRCM)
    McGill University)

  • Eva Cai

    (University of California, Merced)

  • Jingyi Zhang

    (University of California, Merced)

  • Wei-Ju Chen

    (Montreal Clinical Research Institute (IRCM)
    McGill University)

  • 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
    Chan Zuckerberg Biohub)

  • Tess C. Branon

    (Stanford University
    Chan Zuckerberg Biohub
    Interline Therapeutics)

  • Michel Cayouette

    (Montreal Clinical Research Institute (IRCM)
    McGill University
    University of Montreal)

  • Risako Gen

    (University of Washington)

  • Tessa Marks

    (University of Washington)

  • Jennifer H. Kong

    (University of Washington)

  • Frédéric Charron

    (Montreal Clinical Research Institute (IRCM)
    McGill University
    University of Montreal)

  • Xuecai Ge

    (University of California, Merced)

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.

Suggested Citation

  • 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 & M, 2024. "Numb positively regulates Hedgehog signaling at the ciliary pocket," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47244-1
    DOI: 10.1038/s41467-024-47244-1
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    References listed on IDEAS

    as
    1. Jingwu Xie & Maximilien Murone & Shiuh-Ming Luoh & Anne Ryan & Qimin Gu & Chaohui Zhang & Jeannette M. Bonifas & Ching-Wan Lam & Mary Hynes & Audrey Goddard & Arnon Rosenthal & Ervin H Epstein & Frede, 1998. "Activating Smoothened mutations in sporadic basal-cell carcinoma," Nature, Nature, vol. 391(6662), pages 90-92, January.
    2. Kevin C. Corbit & Pia Aanstad & Veena Singla & Andrew R. Norman & Didier Y. R. Stainier & Jeremy F. Reiter, 2005. "Vertebrate Smoothened functions at the primary cilium," Nature, Nature, vol. 437(7061), pages 1018-1021, October.
    3. Danwei Huangfu & Aimin Liu & Andrew S. Rakeman & Noel S. Murcia & Lee Niswander & Kathryn V. Anderson, 2003. "Hedgehog signalling in the mouse requires intraflagellar transport proteins," Nature, Nature, vol. 426(6962), pages 83-87, November.
    4. Petur H. Petersen & Kaiyong Zou & Joseph K. Hwang & Yuh Nung Jan & Weimin Zhong, 2002. "Progenitor cell maintenance requires numb and numblike during mouse neurogenesis," Nature, Nature, vol. 419(6910), pages 929-934, October.
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