Journal
EMBO REPORTS
Volume 16, Issue 11, Pages 1548-1562Publisher
WILEY
DOI: 10.15252/embr.201540374
Keywords
astrogliogenesis; Down syndrome; DYRK1A; neocortical progenitor; STAT
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Mitsubishi Foundation, Takeda Science Foundation
- Daiichi Sankyo Foundation of Life Science
- Canadian Institutes of Health Research
- Grants-in-Aid for Scientific Research [26640005, 15K06697] Funding Source: KAKEN
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Down syndrome (DS) arises from triplication of genes on human chromosome 21 and is associated with anomalies in brain development such as reduced production of neurons and increased generation of astrocytes. Here, we show that differentiation of cortical progenitor cells into astrocytes is promoted by DYRK1A, a Ser/Thr kinase encoded on human chromosome 21. In the Ts1Cje mouse model of DS, increased dosage of DYRK1A augments the propensity of progenitors to differentiate into astrocytes. This tendency is associated with enhanced astrogliogenesis in the developing neocortex. We also find that overexpression of DYRK1A upregulates the activity of the astrogliogenic transcription factor STAT in wild-type progenitors. Ts1Cje progenitors exhibit elevated STAT activity, and depletion of DYRK1A in these cells reverses the deregulation of STAT. In sum, our findings indicate that potentiation of the DYRK1A-STAT pathway in progenitors contributes to aberrant astrogliogenesis in DS.
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