1. Cell Biology
  2. Stem Cells and Regenerative Medicine
Download icon

BLOS2 negatively regulates Notch signaling during neural and hematopoietic stem and progenitor cell development

  1. Wenwen Zhou
  2. Qiuping He
  3. Chunxia Zhang
  4. Xin He
  5. Zongbin Cui
  6. Feng Liu  Is a corresponding author
  7. Wei Li  Is a corresponding author
  1. Chinese Academy of Sciences, China
Research Article
  • Cited 17
  • Views 2,013
  • Annotations
Cite this article as: eLife 2016;5:e18108 doi: 10.7554/eLife.18108

Abstract

Notch signaling plays a crucial role in the control of proliferation and differentiation of stem and progenitor cells during embryogenesis or organogenesis, but its regulation is incompletely understood. BLOS2, encoded by the Bloc1s2 gene, is a shared subunit of two lysosomal trafficking complexes, biogenesis of lysosome-related organelles complex-1 (BLOC-1) and BLOC-1 related complex. Bloc1s2-/- mice were embryonic lethal and exhibited defects in cortical development and hematopoiesis. Loss of BLOS2 resulted in elevated Notch signaling, which consequently increased the proliferation of neural progenitor cells and inhibited neuronal differentiation in cortices. Likewise, ablation of bloc1s2 in zebrafish or mice led to increased hematopoietic stem and progenitor cell production in the aorta-gonad-mesonephros region. BLOS2 physically interacted with Notch1 in endo-lysosomal trafficking of Notch1. Our findings suggest that BLOS2 is a novel negative player in regulating Notch signaling through lysosomal trafficking by controlling multiple stem and progenitor cell homeostasis in vertebrates.

Article and author information

Author details

  1. Wenwen Zhou

    State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Qiuping He

    State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Chunxia Zhang

    State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Xin He

    State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Zongbin Cui

    State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Feng Liu

    State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    For correspondence
    liuf@ioz.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  7. Wei Li

    State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
    For correspondence
    wli@genetics.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7430-6019

Funding

National Natural Science Foundation of China (91539204)

  • Wei Li

National Natural Science Foundation of China (31230046)

  • Wei Li

National Natural Science Foundation of China (31471333)

  • Xin He

National Natural Science Foundation of China (31271570)

  • Feng Liu

Chinese Academy of Sciences (KJZD-EW-L08)

  • Wei Li

Ministry of Science and Technology of the People's Republic of China (2010CB945300)

  • Feng Liu

Chinese Academy of Sciences (XDA01010110)

  • Feng Liu

National Natural Science Foundation of China (31425016)

  • Feng Liu

Ministry of Science and Technology of the People's Republic of China (2011CB943900)

  • Feng Liu

National Natural Science Foundation of China (91332116)

  • Wei Li

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

Ethics

Animal experimentation: All animal procedures were approved by the Institutional Animal Care and Use Committees of IGDB or IOZ, CAS (protocol number: KYD2006-002).

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: May 23, 2016
  2. Accepted: October 4, 2016
  3. Accepted Manuscript published: October 10, 2016 (version 1)
  4. Version of Record published: November 3, 2016 (version 2)

Copyright

© 2016, Zhou 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.

Metrics

  • 2,013
    Page views
  • 635
    Downloads
  • 17
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Neuroscience
    Javier Emperador-Melero et al.
    Research Advance

    It has long been proposed that Leukocyte common Antigen-Related Receptor Protein Tyrosine Phosphatases (LAR-RPTPs) are cell-adhesion proteins that control synapse assembly. Their synaptic nanoscale localization, however, is not established, and synapse fine structure after knockout of the three vertebrate LAR-RPTPs (PTPδ, PTPσ and LAR) has not been tested. Here, superresolution microscopy reveals that PTPδ localizes to the synaptic cleft precisely apposed to postsynaptic scaffolds of excitatory and inhibitory synapses. We next assessed synapse structure in newly generated triple-conditional knockout mice for PTPδ, PTPσ and LAR, complementing a recent independent study of synapse function after LAR-RPTP ablation (Sclip and Südhof, 2020). While mild effects on synaptic vesicle clustering and active zone architecture were detected, synapse numbers and their overall structure were unaffected, membrane anchoring of the active zone persisted, and vesicle docking and release were normal. Hence, despite their localization at synaptic appositions, LAR-RPTPs are dispensable for presynapse structure and function.

    1. Cell Biology
    2. Stem Cells and Regenerative Medicine
    Carolina Ortiz-Cordero et al.
    Research Article Updated

    Mutations in the fukutin-related protein (FKRP) cause Walker-Warburg syndrome (WWS), a severe form of congenital muscular dystrophy. Here, we established a WWS human induced pluripotent stem cell-derived myogenic model that recapitulates hallmarks of WWS pathology. We used this model to investigate the therapeutic effect of metabolites of the pentose phosphate pathway in human WWS. We show that functional recovery of WWS myotubes is promoted not only by ribitol but also by its precursor ribose. Moreover, we found that the combination of each of these metabolites with NAD+ results in a synergistic effect, as demonstrated by rescue of α-dystroglycan glycosylation and laminin binding capacity. Mechanistically, we found that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analyses. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.