HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development

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.

Data availability

The following data sets were generated

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.

Metrics

  • 2,419
    Page views
  • 346
    Downloads
  • 33
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, 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)

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. Marisa Connell
  2. Helen Chen
  3. Jihong Jiang
  4. Chia-Wei Kuan
  5. Abbas Fotovati
  6. Tony Chu
  7. Zhengcheng He
  8. Tess C Lengyell
  9. Huaibiao Li
  10. Torsten Kroll
  11. Amanda M Li
  12. Daniel Goldowitz
  13. Lucien Frappart
  14. Aspasia Ploubidou
  15. Millan Patel
  16. Linda M Pilarski
  17. Elizabeth M Simpson
  18. Philipp Lange
  19. Douglas Watt Allan
  20. Christopher A Maxwell
(2017)
HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development
eLife 6:e28672.
https://doi.org/10.7554/eLife.28672

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Liangyu Zhang, Weston T Stauffer ... Abby F Dernburg
    Research Article

    Meiotic chromosome segregation relies on synapsis and crossover recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in 'homolog engagement' is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans, recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break induction. Inactivation of CHK-2 terminates double-strand break formation and enables crossover designation and cell cycle progression. These findings illuminate how meiotic cells ensure crossover formation and accurate chromosome segregation.

    1. Cell Biology
    2. Physics of Living Systems
    Christa Ringers, Stephan Bialonski ... Nathalie Jurisch-Yaksi
    Research Article

    Motile cilia are hair-like cell extensions that beat periodically to generate fluid flow along various epithelial tissues within the body. In dense multiciliated carpets, cilia were shown to exhibit a remarkable coordination of their beat in the form of traveling metachronal waves, a phenomenon which supposedly enhances fluid transport. Yet, how cilia coordinate their regular beat in multiciliated epithelia to move fluids remains insufficiently understood, particularly due to lack of rigorous quantification. We combine experiments, novel analysis tools, and theory to address this knowledge gap. To investigate collective dynamics of cilia, we studied zebrafish multiciliated epithelia in the nose and the brain. We focused mainly on the zebrafish nose, due to its conserved properties with other ciliated tissues and its superior accessibility for non-invasive imaging. We revealed that cilia are synchronized only locally and that the size of local synchronization domains increases with the viscosity of the surrounding medium. Even though synchronization is local only, we observed global patterns of traveling metachronal waves across the zebrafish multiciliated epithelium. Intriguingly, these global wave direction patterns are conserved across individual fish, but different for left and right nose, unveiling a chiral asymmetry of metachronal coordination. To understand the implications of synchronization for fluid pumping, we used a computational model of a regular array of cilia. We found that local metachronal synchronization prevents steric collisions, cilia colliding with each other, and improves fluid pumping in dense cilia carpets, but hardly affects the direction of fluid flow. In conclusion, we show that local synchronization together with tissue-scale cilia alignment coincide and generate metachronal wave patterns in multiciliated epithelia, which enhance their physiological function of fluid pumping.