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

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 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.

Single-cell transcriptome profiling of thyroid hormone effectors in the human fetal neocortex: expression of SLCO1C1, DIO2, and THRB in specific cell types

“…In rodents, hypothyroidism affects radial glial cells (22). THRA mutations cause abnormal adhesion and proliferation of human cortical progenitors (23), suggesting alterations in the radial glia. Radial glial cells are immunoreactive for MCT8 and OATP1C1 in human fetal brain slices (9).…”

Best Achievements in Translational and Basic Thyroidology in 2020

“…Thyroid hormone receptor alpha mutations Two intriguing studies using novel models of thyroid hormone receptor alpha (THRA) mutations, which cause thyroid hormone resistance syndrome (RTH), were published in 2020. Krieger et al [1] demonstrated the essential actions of thyroid hormone receptor alpha (TRα) on the normal development of the human cerebral cortex. The authors previously reported that adult patients with RTH had intellectual impairments, especially affecting nonverbal IQ and delayed sensorimotor processing [2].…”

“…Indeed, these findings were consistent with those of a mouse model with a mutant variant of TRα1, which showed a range of central nervous system abnormalities [3], but the cellular mechanisms of the impacts of THRA (the gene encoding TRα) on neural development remained unclear. Krieger et al [1], using THRA mutant patient-derived induced pluripotent stem cell (iPS) models in combination with a quantitative lineage analysis, gene expression analysis, and novel assays of neuro-epithelium formation, showed that THRA regulates the balance between progenitor self-renewal and neurogenesis, thereby affecting the overall brain mass and especially the cortex. A structural www.e-enm.org 37 modeling study of the ligand-binding domain of TRα1 demonstrated that the THRA mutation facilitates corepressor binding.…”