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

Krieger, TG; Moran, CM; Frangini, A; Visser, WE; Schoenmakers, E; Muntoni, F; Clark, CA; ... Livesey, FJ; + view all (2019) Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development. Proceedings of the National Academy of Sciences of the United States of America , 116 (45) pp. 22754-22763. 10.1073/pnas.1908762116. Green open access

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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.

Type: Article
Title: Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1908762116
Publisher version: https://doi.org/10.1073/pnas.1908762116
Language: English
Additional information: This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/
Keywords: brain development, iPSCs, thyroid hormone
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10084536
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