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

Abstract

Background: Thyroid hormones are crucial for brain development, acting through the thyroid hormone nuclear receptors (TR) α1 and β to control gene expression. 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 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. Methods:We analyzed publicly available single-cell transcriptome datasets 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. Results:The radial glia, mainly the outer radial glia, and astrocytes coexpress SLCO1C1 and DIO2, indicating close cooperation between the T4 transporter OATP1C1 and DIO2 in local T3 formation. Strikingly, THRB was mainly present in two classes of interneurons: a majority expressing CALB2/calretinin, from the caudal ganglionic eminence, and in somatostatin-expressing interneurons from the medial ganglionic eminence. By contrast, many cell types express SLC16A2 and THRA.Conclusions: SLCO1C1 and DIO2 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 THRB in discrete subsets of interneurons is a novel finding whose pathophysiological meaning deserves further investigation.

Thyroid hormone regulators in human cerebral cortex development

“…We analyzed five single-cell RNA-Seq datasets from the human fetal cerebral cortex to look for specific expressions of thyroid regulators (Pollen et al 2015, Nowakowski et al 2017, Zhong et al 2018, Polioudakis et al 2019, Shi et al 2021. Results from these different datasets gave similar results (Diez et al 2021). For this reason, only two of them will be reviewed here (Pollen et al 2015, Polioudakis et al 2019.…”

“…In all cases, we used the original raw data and followed similar pipelines (Diez et al 2021). The first step was the normalization and identification of the topmost highly variable genes.…”

“…These pathways are developmentally regulated (Gereben et al 2008), and the timing and cell type-specific expression are essential clues to understanding the action of thyroid hormones during development. In this paper, we will analyze the development of the human neocortex in the context of thyroid pathophysiology and review recent work on the expression of thyroid hormone transporters, deiodinases, and receptors through transcriptomic profiling using single-cell RNA-Seq datasets (Diez et al 2021). This paper summarizes a presentation given at the 24th European Congress of Endocrinology, Milan, May 22-24, 2022. humans (Bystron et al 2008, Defelipe 2011.…”

T3 levels and thyroid hormone signaling

“…For example, the basal metabolic rate reflects T3 action in metabolically relevant tissues, the serum cholesterol or SHGB levels, and the myocardial isometric contraction time, which reflects T3 action in the liver and heart, respectively. More recently, the utilization of single-cell RNA-seq data and proteomic tools have allowed for identifying cell types sensitive to TH regulation in tissues and accurate tissue-specific biomarkers of TH action that await clinical validation ( 52 – 54 ).…”

A Pathway for T3 Signaling in the Brain to Improve the Variable Effectiveness of Therapy With L-T4

“…TH are crucial for brain development and influence brain function throughout life (3)(4)(5). However, the complex architectural organization of the brain and unique properties of each cell type pose a challenge to the complete understanding of the mechanisms that regulate local TH signaling (6). Neurons are an important TH target in the brain as they express the highest levels of TH receptors (TRs) (7).…”