Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells

Download
Author
Bellmaine, SF; Ovchinnikov, DA; Manallack, DT; Cuddy, CE; Elefanty, AG; Stanley, EG; Wolvetang, EJ; Williams, SJ; Pera, MDate
2017-09-08Source Title
eLifePublisher
ELIFE SCIENCES PUBLICATIONS LTDUniversity of Melbourne Author/s
Pera, Martin; Stanley, Edouard; Elefanty, Andrew; Williams, Spencer; Bellmaine, Stephanie; Cuddy, ClaireAffiliation
Anatomy and NeuroscienceSchool of Chemistry
Paediatrics (RCH)
Metadata
Show full item recordDocument Type
Journal ArticleCitations
Bellmaine, S. F., Ovchinnikov, D. A., Manallack, D. T., Cuddy, C. E., Elefanty, A. G., Stanley, E. G., Wolvetang, E. J., Williams, S. J. & Pera, M. (2017). Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells. ELIFE, 6, https://doi.org/10.7554/eLife.24502.Access Status
Open AccessAbstract
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.
Export Reference in RIS Format
Endnote
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
Refworks
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References