1. Cell Biology
  2. Developmental Biology
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HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development

Research Article
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Cite this article as: eLife 2017;6:e28672 doi: 10.7554/eLife.28672

Abstract

Oriented cell division is one mechanism progenitor cells use during development and to maintain tissue homeostasis. Common to most cell types is the asymmetric establishment and regulation of cortical NuMA-dynein complexes that position the mitotic spindle. Here, we discover that HMMR acts at centrosomes in a PLK1-dependent pathway that locates active Ran and modulates the cortical localization of NuMA-dynein complexes to correct mispositioned spindles. This pathway was discovered through the creation and analysis of Hmmr-knockout mice, which suffer neonatal lethality with defective neural development and pleiotropic phenotypes in multiple tissues. HMMR over-expression in immortalized cancer cells induces phenotypes consistent with an increase in active Ran including defects in spindle orientation. These data identify an essential role for HMMR in the PLK1-dependent regulatory pathway that orients progenitor cell division and supports neural development.

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Article and author information

Author details

  1. Marisa Connell

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Helen Chen

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Jihong Jiang

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Chia-Wei Kuan

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Abbas Fotovati

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Tony Chu

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhengcheng He

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Tess C Lengyell

    Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Huaibiao Li

    Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4086-3321
  10. Torsten Kroll

    Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Amanda M Li

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Daniel Goldowitz

    Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Lucien Frappart

    Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Aspasia Ploubidou

    Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Millan Patel

    Department of Medical Genetics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  16. Linda M Pilarski

    Department of Oncology, University of Alberta, Edmonton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Elizabeth M Simpson

    Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  18. Philipp Lange

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  19. Douglas Watt Allan

    Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  20. Christopher A Maxwell

    Department of Paediatrics, University of British Columbia, Vancouver, Canada
    For correspondence
    cmaxwell@bcchr.ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0860-4031

Funding

Canadian Institutes of Health Research (OBC 134038)

  • Christopher A Maxwell

Michael Cuccione Foundation

  • Marisa Connell
  • Helen Chen
  • Christopher A Maxwell

Canadian Breast Cancer Foundation

  • Tony Chu

Child and Family Research Institute

  • Zhengcheng He
  • Christopher A Maxwell

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 procedures involving animals were in accordance with the Canadian Council on Animal Care (CCAC) and UBC Animal Care Committee (ACC) (Protocol no. A13-0168).

Reviewing Editor

  1. Iain M Cheeseman, Whitehead Institute, United States

Publication history

  1. Received: May 16, 2017
  2. Accepted: October 5, 2017
  3. Accepted Manuscript published: October 10, 2017 (version 1)
  4. Version of Record published: November 10, 2017 (version 2)

Copyright

© 2017, Connell 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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