The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating notch receptor trafficking
- Peking University, China
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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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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.
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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The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating notch receptor trafficking
eLife 7:e38181.
https://doi.org/10.7554/eLife.38181
