The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating notch receptor trafficking

Abstract

The correct establishment and maintenance of unidirectional Notch signaling are critical for the homeostasis of various stem cell lineages. However, the molecular mechanisms that prevent cell-autonomous ectopic Notch signaling activation and deleterious cell fate decisions remain unclear. Here we show that the retromer complex directly and specifically regulates Notch receptor retrograde trafficking in Drosophila neuroblast lineages to ensure the unidirectional Notch signaling from neural progenitors to neuroblasts. Notch polyubiquitination mediated by E3 ubiquitin ligase Itch/Su(dx) is inherently inefficient within neural progenitors, relying on retromer-mediated trafficking to avoid aberrant endosomal accumulation of Notch and cell-autonomous signaling activation. Upon retromer dysfunction, hypo-ubiquitinated Notch accumulates in Rab7+ enlarged endosomes, where it is ectopically processed and activated in a ligand-dependent manner, causing progenitor-originated tumorigenesis. Our results therefore unveil a safeguard mechanism whereby retromer retrieves potentially harmful Notch receptors in a timely manner to prevent aberrant Notch activation-induced neural progenitor dedifferentiation and brain tumor formation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Bo Li

    Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Chouin Wong

    School Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life SciencesLife Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Shihong Max Gao

    Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Rulan Zhang

    Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Rongbo Sun

    State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yulong Li

    Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yan Song

    Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
    For correspondence
    yan.song@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1413-6123

Funding

National Natural Science Foundation of China (31471372)

  • Yan Song

the Peking-Tsinghua Center for Life Sciences

  • Yan Song

the Ministry of Education Key Laboratory of Cell Proliferation and Differentiation

  • Yan Song

National Natural Science Foundation of China (31771629)

  • Yan Song

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Thomas Vaccari

Publication history

  1. Received: May 8, 2018
  2. Accepted: August 17, 2018
  3. Accepted Manuscript published: September 4, 2018 (version 1)
  4. Version of Record published: September 14, 2018 (version 2)

Copyright

© 2018, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Bo Li
  2. Chouin Wong
  3. Shihong Max Gao
  4. Rulan Zhang
  5. Rongbo Sun
  6. Yulong Li
  7. Yan Song
(2018)
The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating notch receptor trafficking
eLife 7:e38181.
https://doi.org/10.7554/eLife.38181

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