期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 45, 页码 22754-22763出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908762116
关键词
thyroid hormone; brain development; iPSCs
资金
- Engineering and Physical Sciences Research Council
- Raymond and Beverly Sackler Foundation
- National Institute of Health Research, Cambridge Biomedical Centre
- Wellcome Trust
- Cancer Research UK
- MRC [MR/L023784/2, G0300117, G0600717, G1002276, MR/L023784/1] Funding Source: UKRI
Mutations in the thyroid hormone receptor alpha 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutationcontaining progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell-cell adhesion genes. These results reveal that thyroid hormone receptor alpha 1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.
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