1. Developmental Biology and Stem Cells
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Inhibition of DYRK1A disrupts neural lineage specification in human pluripotent stem cells

  1. Stephanie F Bellmaine
  2. Dmitry A Ovchinnikov
  3. David T Manallack
  4. Claire E Cuddy
  5. Andrew G Elefanty
  6. Edouard G Stanley
  7. Ernst J Wolvetang
  8. Spencer J Williams
  9. Martin Pera Is a corresponding author
  1. University of Melbourne, Australia
  2. University of Queensland, Australia
  3. Monash Institute of Pharmaceutical Sciences, Monash University, Australia
  4. Murdoch Childrens Research Institute, The Royal Children's Hospital, Australia
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Cite as: eLife 2017;6:e24502 doi: 10.7554/eLife.24502

Abstract

Genetic analysis has revealed that the dual specificity protein kinase DYRK1A has multiple roles in the development of the central nervous system. Increased DYRK1A gene dosage, such as occurs in Down syndrome, affects neural progenitor cell differentiation, while haploinsufficiency of DYRK1A is associated with severe microcephaly. Using a set of known and newly synthesized DYRK1A inhibitors, along with CRISPR-mediated gene activation and shRNA knockdown of DYRK1A, we show that chemical inhibition or genetic knockdown of DYRK1A interferes with neural specification of human pluripotent stem cells, a process equating to the earliest stage of human brain development. DYRK1A inhibition insulates the self-renewing subpopulation of human pluripotent stem cells from powerful signals that drive neural induction. Our results suggest a novel mechanism for the disruptive effects of loss of DYRK1A during early mammalian development, and reveal a requirement for DYRK1A in the acquisition of competence for differentiation in human pluripotent stem cells.

Article and author information

Author details

  1. Stephanie F Bellmaine

    School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia
    Competing interests
    No competing interests declared.
  2. Dmitry A Ovchinnikov

    Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Queensland, Australia
    Competing interests
    No competing interests declared.
  3. David T Manallack

    Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia
    Competing interests
    No competing interests declared.
  4. Claire E Cuddy

    Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.
  5. Andrew G Elefanty

    Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Australia
    Competing interests
    No competing interests declared.
  6. Edouard G Stanley

    Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Australia
    Competing interests
    No competing interests declared.
  7. Ernst J Wolvetang

    Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Queensland, Australia
    Competing interests
    No competing interests declared.
    ORCID icon 0000-0002-2146-6614
  8. Spencer J Williams

    School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia
    Competing interests
    No competing interests declared.
  9. Martin Pera

    Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia
    For correspondence
    mpera@unimelb.edu.au
    Competing interests
    Martin Pera, Reviewing editor, eLife.
    ORCID icon 0000-0001-6239-0428

Funding

Australian Research Council (Special Research Initiative SR1101002)

  • Dmitry A Ovchinnikov
  • Andrew G Elefanty
  • Edouard G Stanley
  • Ernst J Wolvetang
  • Martin Pera

National Health and Medical Research Council (Senior Research Fellowship)

  • Andrew G Elefanty
  • Edouard G Stanley

University of Melbourne (Strategic APA)

  • Stephanie F Bellmaine
  • Spencer J Williams
  • Martin Pera

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

Reviewing Editor

  1. Lee L Rubin, Reviewing Editor, Harvard Stem Cell Institute, Harvard University, United States

Publication history

  1. Received: December 22, 2016
  2. Accepted: September 1, 2017
  3. Accepted Manuscript published: September 8, 2017 (version 1)

Copyright

© 2017, Bellmaine 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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