WDR62 regulates early neural and glial progenitor specification of human pluripotent stem cells

Alshawaf, Abdulah J., Antonic, Ana, Skafidas, Efstratios, Ng, Dominic Chi-Hung and Dottori, Mirella (2017) WDR62 regulates early neural and glial progenitor specification of human pluripotent stem cells. Stem Cells International, 2017 7848932. doi:10.1155/2017/7848932

Author Alshawaf, Abdulah J.
Antonic, Ana
Skafidas, Efstratios
Ng, Dominic Chi-Hung
Dottori, Mirella
Title WDR62 regulates early neural and glial progenitor specification of human pluripotent stem cells
Journal name Stem Cells International   Check publisher's open access policy
ISSN 1687-966X
Publication date 2017-01-01
Sub-type Article (original research)
DOI 10.1155/2017/7848932
Open Access Status DOI
Volume 2017
Start page 7848932
Total pages 9
Place of publication New York, NY, United States
Publisher Hindawi
Language eng
Subject 1312 Molecular Biology
1307 Cell Biology
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.
Formatted abstract
Mutations in WD40-repeat protein 62 (WDR62) are commonly associated with primary microcephaly and other developmental cortical malformations. We used human pluripotent stem cells (hPSC) to examine WDR62 function during human neural differentiation and model early stages of human corticogenesis. Neurospheres lacking WDR62 expression showed decreased expression of intermediate progenitor marker, TBR2, and also glial marker, S100β. In contrast, inhibition of c-Jun N-terminal kinase (JNK) signalling during hPSC neural differentiation induced upregulation of WDR62 with a corresponding increase in neural and glial progenitor markers, PAX6 and EAAT1, respectively. These findings may signify a role of WDR62 in specifying intermediate neural and glial progenitors during human pluripotent stem cell differentiation.
Keyword General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Neuroscience
General Medicine
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID Special Research Initiative SR1101002
Senior Research Fellowship
Strategic APA
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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