Single-Cell Transcriptome Profiling of Thyroid Hormone Effectors in the Human Fetal Neocortex: Expression of , , and in Specific Cell Types.

Thyroid hormones are crucial for brain development, acting through the thyroid hormone nuclear receptors (TR)α1 and β to control gene expression. Triiodothyronine (T3), the receptor-ligand, is transported into the brain from the blood by the monocarboxylate transporter 8 (MCT8). Another source of brain T3 is from the local deiodination of thyroxine (T4) by type 2 deiodinase (DIO2). While these mechanisms are very similar in mice and humans, important species-specific differences confound our understanding of disease using mouse models. To fill this knowledge gap on thyroid hormone action in the human fetal brain, we analyzed the expression of transporters, DIO2, and TRs, which we call thyroid hormone effectors, at single-cell resolution. We analyzed publicly available single-cell transcriptome data sets of isolated cerebral cortex neural cells from three different studies, with expression data from 393 to almost 40,000 cells. We generated Uniform Manifold Approximation and Projection scatterplots and cell clusters to identify differentially expressed genes between clusters, and correlated their gene signatures with the expression of thyroid effectors. The radial glia, mainly the outer radial glia, and astrocytes coexpress and indicating close cooperation between the T4 transporter OATP1C1 and DIO2 in local T3 formation. Strikingly, was mainly present in two classes of interneurons: a majority expressing /calretinin, from the caudal ganglionic eminence, and in somatostatin-expressing interneurons from the medial ganglionic eminence. By contrast, many cell types express and . and coexpression in the outer radial glia, the universal stem cell of the cerebral cortex, highlights the likely importance of brain-generated T3 in neurogenesis. The unique expression of in discrete subsets of interneurons is a novel finding whose pathophysiological meaning deserves further investigation.