Inhibition of DYRK1A disrupts neural lineage specification in human pluripotent stem cells

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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.

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Stephanie F Bellmaine

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia

Competing interests
No competing interests declared.
Dmitry A Ovchinnikov

Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Queensland, Australia

Competing interests
No competing interests declared.
David T Manallack

Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia

Competing interests
No competing interests declared.
Claire E Cuddy

Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia

Competing interests
No competing interests declared.
Andrew G Elefanty

Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Australia

Competing interests
No competing interests declared.
Edouard G Stanley

Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Australia

Competing interests
No competing interests declared.
Ernst J Wolvetang

Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Queensland, Australia

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-2146-6614
Spencer J Williams

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia

Competing interests
No competing interests declared.
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.

"This ORCID iD identifies the author of this article:" 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.

Copyright

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.