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

  • 2,305
    Page views
  • 324
    Downloads
  • 31
    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
    Tai-De Li et al.
    Research Article

    Branched actin networks are self-assembling molecular motors that move biological membranes and drive many important cellular processes, including phagocytosis, endocytosis, and pseudopod protrusion. When confronted with opposing forces, the growth rate of these networks slows and their density increases, but the stoichiometry of key components does not change. The molecular mechanisms governing this force response are not well understood, so we used single-molecule imaging and AFM cantilever deflection to measure how applied forces affect each step in branched actin network assembly. Although load forces are observed to increase the density of growing filaments, we find that they actually decrease the rate of filament nucleation due to inhibitory interactions between actin filament ends and nucleation promoting factors. The force-induced increase in network density turns out to result from an exponential drop in the rate constant that governs filament capping. The force dependence of filament capping matches that of filament elongation and can be explained by expanding Brownian Ratchet theory to cover both processes. We tested a key prediction of this expanded theory by measuring the force-dependent activity of engineered capping protein variants and found that increasing the size of the capping protein increases its sensitivity to applied forces. In summary, we find that Brownian Ratchets underlie not only the ability of growing actin filaments to generate force but also the ability of branched actin networks to adapt their architecture to changing loads.

    1. Cell Biology
    2. Immunology and Inflammation
    Ekaterini Maria Lyras et al.
    Research Article

    The tongue is a unique muscular organ situated in the oral cavity where it is involved in taste sensation, mastication, and articulation. As a barrier organ, which is constantly exposed to environmental pathogens, the tongue is expected to host an immune cell network ensuring local immune defence. However, the composition and the transcriptional landscape of the tongue immune system are currently not completely defined. Here, we characterised the tissue-resident immune compartment of the murine tongue during development, health and disease, combining single-cell RNA-sequencing with in situ immunophenotyping. We identified distinct local immune cell populations and described two specific subsets of tongue-resident macrophages occupying discrete anatomical niches. Cx3cr1+ macrophages were located specifically in the highly innervated lamina propria beneath the tongue epidermis and at times in close proximity to fungiform papillae. Folr2+ macrophages were detected in deeper muscular tissue. In silico analysis indicated that the two macrophage subsets originate from a common proliferative precursor during early postnatal development and responded differently to systemic LPS in vivo. Our description of the under-investigated tongue immune system sets a starting point to facilitate research on tongue immune-physiology and pathology including cancer and taste disorders.