RT Journal Article
SR Electronic
T1 Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 529677
DO 10.1101/529677
A1 Teresa G Krieger
A1 Carla M Moran
A1 Alberto Frangini
A1 W Edward Visser
A1 Erik Schoenmakers
A1 Francesco Muntoni
A1 Chris Clark
A1 David Gadian
A1 Wui K Chong
A1 Adam Kuczynski
A1 Mehul Dattani
A1 Greta Lyons
A1 Alexandra Efthymiadou
A1 Faraneh Varga-Khadem
A1 Benjamin D Simons
A1 Krishna Chatterjee
A1 Frederick J Livesey
YR 2019
UL http://biorxiv.org/content/early/2019/01/26/529677.abstract
AB 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 microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs 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 novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation and organisation in human cerebral cortical development. They also exemplify novel quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.