1. Cell Biology
  2. Developmental Biology

Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division

  1. Cuie Chen
  2. Ryan Cummings
  3. Aghapi Mordovanakis
  4. Alan J Hunt
  5. Michael Mayer
  6. David Sept
  7. Yukiko M Yamashita  Is a corresponding author
  1. University of Michigan, United States
https://doi.org/10.7554/eLife.33685
Share this article
Cite this article
  1. Cuie Chen
  2. Ryan Cummings
  3. Aghapi Mordovanakis
  4. Alan J Hunt
  5. Michael Mayer
  6. David Sept
  7. Yukiko M Yamashita
(2018)
Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division
eLife 7:e33685.
https://doi.org/10.7554/eLife.33685
  2. Download BibTeX
  3. Download .RIS

Abstract

Asymmetric stem cell division is a critical mechanism for balancing self-renewal and differentiation. Adult stem cells often orient their mitotic spindle to place one daughter inside the niche and the other outside of it to achieve asymmetric division. It remains unknown whether and how the niche may direct division orientation. Here we discover a novel and evolutionary conserved mechanism that couples cell polarity to cell fate. We show that the cytokine receptor homolog Dome, acting downstream of the niche-derived ligand Upd, directly binds to the microtubule-binding protein Eb1 to regulate spindle orientation in Drosophila male germline stem cells (GSCs). Dome's role in spindle orientation is entirely separable from its known function in self-renewal mediated by the JAK-STAT pathway. We propose that integration of two functions (cell polarity and fate) in a single receptor is a key mechanism to ensure an asymmetric outcome following cell division.

Article and author information

Author details

  1. Cuie Chen

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.

  2. Ryan Cummings

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.

  3. Aghapi Mordovanakis

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.

  4. Alan J Hunt

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.

  5. Michael Mayer

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.

  6. David Sept

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.

  7. Yukiko M Yamashita

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    For correspondence
    yukikomy@umich.edu
    Competing interests
    Yukiko M Yamashita, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5541-0216

Funding

Howard Hughes Medical Institute

  • Yukiko M Yamashita

National Institute of General Medical Sciences (R01GM07200606)

  • Alan J Hunt
  • Michael Mayer
  • Yukiko M Yamashita

National Institute of General Medical Sciences (R01GM118308)

  • Yukiko M Yamashita

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

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Version history

  1. Received: November 18, 2017
  2. Accepted: March 25, 2018
  3. Accepted Manuscript published: March 26, 2018 (version 1)
  4. Version of Record published: April 5, 2018 (version 2)

Copyright

© 2018, Chen 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

  • 2,237
    views
  • 398
    downloads
  • 14
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Cuie Chen
  2. Ryan Cummings
  3. Aghapi Mordovanakis
  4. Alan J Hunt
  5. Michael Mayer
  6. David Sept
  7. Yukiko M Yamashita
(2018)
Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division
eLife 7:e33685.
https://doi.org/10.7554/eLife.33685

Share this article

https://doi.org/10.7554/eLife.33685

Categories and tags

Research organism

Further reading

    1. Cell Biology

    A genome-wide CRISPR/Cas9 screen identifies calreticulin as a selective repressor of ATF6α

    Joanne Tung, Lei Huang ... Adriana Ordonez
    Research Article

    Activating transcription factor 6 (ATF6) is one of three endoplasmic reticulum (ER) transmembrane stress sensors that mediate the unfolded protein response (UPR). Despite its crucial role in long-term ER stress adaptation, regulation of ATF6 alpha (α) signalling remains poorly understood, possibly because its activation involves ER-to-Golgi and nuclear trafficking. Here, we generated an ATF6α/Inositol-requiring kinase 1 (IRE1) dual UPR reporter CHO-K1 cell line and performed an unbiased genome-wide CRISPR/Cas9 mutagenesis screen to systematically profile genetic factors that specifically contribute to ATF6α signalling in the presence and absence of ER stress. The screen identified both anticipated and new candidate genes that regulate ATF6α activation. Among these, calreticulin (CRT), a key ER luminal chaperone, selectively repressed ATF6α signalling: Cells lacking CRT constitutively activated a BiP::sfGFP ATF6α-dependent reporter, had higher BiP levels and an increased rate of trafficking and processing of ATF6α. Purified CRT interacted with the luminal domain of ATF6α in vitro and the two proteins co-immunoprecipitated from cell lysates. CRT depletion exposed a negative feedback loop implicating ATF6α in repressing IRE1 activity basally and overexpression of CRT reversed this repression. Our findings indicate that CRT, beyond its known role as a chaperone, also serves as an ER repressor of ATF6α to selectively regulate one arm of the UPR.

    1. Cancer Biology
    2. Cell Biology

    A syngeneic spontaneous zebrafish model of tp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapse in vivo

    Alex Weiss, Cassandra D'Amata ... Madeline N Hayes
    Research Article

    High-throughput vertebrate animal model systems for the study of patient-specific biology and new therapeutic approaches for aggressive brain tumors are currently lacking, and new approaches are urgently needed. Therefore, to build a patient-relevant in vivo model of human glioblastoma, we expressed common oncogenic variants including activated human EGFRvIII and PI3KCAH1047R under the control of the radial glial-specific promoter her4.1 in syngeneic tp53 loss-of-function mutant zebrafish. Robust tumor formation was observed prior to 45 days of life, and tumors had a gene expression signature similar to human glioblastoma of the mesenchymal subtype, with a strong inflammatory component. Within early stage tumor lesions, and in an in vivo and endogenous tumor microenvironment, we visualized infiltration of phagocytic cells, as well as internalization of tumor cells by mpeg1.1:EGFP+ microglia/macrophages, suggesting negative regulatory pressure by pro-inflammatory cell types on tumor growth at early stages of glioblastoma initiation. Furthermore, CRISPR/Cas9-mediated gene targeting of master inflammatory transcription factors irf7 or irf8 led to increased tumor formation in the primary context, while suppression of phagocyte activity led to enhanced tumor cell engraftment following transplantation into otherwise immune-competent zebrafish hosts. Altogether, we developed a genetically relevant model of aggressive human glioblastoma and harnessed the unique advantages of zebrafish including live imaging, high-throughput genetic and chemical manipulations to highlight important tumor-suppressive roles for the innate immune system on glioblastoma initiation, with important future opportunities for therapeutic discovery and optimizations.

    1. Cancer Biology
    2. Cell Biology

    Cancer: Modeling glioblastoma

    Ian Lorimer
    Insight

    Establishing a zebrafish model of a deadly type of brain tumor highlights the role of the immune system in the early stages of the disease.