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Proc Natl Acad Sci U S A. 2019 Nov 5;116(45):22754-22763. doi: 10.1073/pnas.1908762116. Epub 2019 Oct 18.

Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development.

Author information

1
Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.
2
Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, United Kingdom.
3
Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
4
Dubowitz Neuromuscular Centre and National Institute for Health Research (NIHR) Great Ormond Street (GOS) Hospital Biomedical Research Centre, London WC1N 1EH, United Kingdom.
5
Developmental Imaging and Biophysics Section, University College London (UCL) GOS Institute of Child Health, London WC1N 1EH, United Kingdom.
6
Department of Radiology, Great Ormond Street Children's Hospital, London WC1N 3JH, United Kingdom.
7
Department of Neuropsychology, Great Ormond Street Children's Hospital, London WC1N 1EH, United Kingdom.
8
Department of Endocrinology, Great Ormond Street Children's Hospital and Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health, London WC1N 1EH, United Kingdom.
9
Department of Endocrinology, University of Ioannina, 45110 Ioannina, Greece.
10
Cognitive Neuroscience and Neuropsychiatry Section, UCL GOS Institute of Child Health, London WC1N 1EH, United Kingdom.
11
Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom; r.livesey@ucl.ac.uk.
12
UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, United Kingdom.

Abstract

Mutations in the thyroid hormone receptor α 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 mutation-containing 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 α1 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.

KEYWORDS:

brain development; iPSCs; thyroid hormone

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