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Elife. 2017 Sep 8;6. pii: e24502. doi: 10.7554/eLife.24502.

Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.

Author information

1
School of Chemistry, University of Melbourne, Victoria, Australia.
2
Department of Anatomy and Neuroscience, University of Melbourne, Victoria, Australia.
3
Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia.
4
Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Australia.
5
Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Victoria, Australia.
6
Murdoch Childrens Research Institute, The Royal Children's Hospital, Victoria, Australia.
7
Department of Anatomy and Neuroscience, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia.
8
Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia.
9
Walter and Eliza Hall Institute of Medical Research, Florey Neuroscience and Mental Health Institute, Victoria, Australia.
#
Contributed equally

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, is known to affect 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 here 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. Specifically, 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 the absence or haploinsufficiency of DYRK1A on early mammalian development, and reveal a requirement for DYRK1A in the acquisition of competence for differentiation in human pluripotent stem cells.

KEYWORDS:

Homo sapiens; developmental biology; none; pluripotent; stem cell; stem cells

PMID:
28884684
PMCID:
PMC5656431
DOI:
10.7554/eLife.24502
[Indexed for MEDLINE]
Free PMC Article

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