Spatiotemporal expression of thyroid hormone transporter MCT8 and THRA mRNA in human cerebral organoids recapitulating first trimester cortex development

• Published in: Scientific reports 2024-04, Vol.14 (1), p.9355-9355, Article 9355
• Main Authors: Graffunder, Adina Sophie, Bresser, Audrey Amber Julie, Fernandez Vallone, Valeria, Megges, Matthias, Stachelscheid, Harald, Kühnen, Peter, Opitz, Robert
• Format: Article
• Language: English
• Subjects: 631/136/368/2430; 692/163/2743/1841; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Cerebral organoids; Cortex; Female; Fluorescence in situ hybridization; Gene expression; Gene Expression Regulation, Developmental; Glial stem cells; Hormones; Human cortex; Humanities and Social Sciences; Humans; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; multidisciplinary; Nervous system; Neural coding; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis; Neurogenesis - genetics; Neuronal-glial interactions; Neurons - metabolism; Organoids; Organoids - metabolism; Phenotypes; Pregnancy; Pregnancy Trimester, First - metabolism; Progenitor cells; Protein expression; Radial glial cells; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Subventricular zone; Symporters - genetics; Symporters - metabolism; Thyroid; Thyroid gland; Thyroid hormone; Thyroid hormone receptor; Thyroid Hormone Receptors alpha - genetics; Thyroid Hormone Receptors alpha - metabolism; Thyroid hormone transporter; Thyroid hormones; Thyroid Hormones - genetics; Thyroid Hormones - metabolism; Triiodothyronine; Ventricular zone
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-59533-2

Thyroid hormones (TH) play critical roles during nervous system development and patients carrying coding variants of MCT8 (monocarboxylate transporter 8) or THRA (thyroid hormone receptor alpha) present a spectrum of neurological phenotypes resulting from perturbed local TH action during early brain development. Recently, human cerebral organoids (hCOs) emerged as powerful in vitro tools for disease modelling recapitulating key aspects of early human cortex development. To begin exploring prospects of this model for thyroid research, we performed a detailed characterization of the spatiotemporal expression of MCT8 and THRA in developing hCOs. Immunostaining showed MCT8 membrane expression in neuronal progenitor cell types including early neuroepithelial cells, radial glia cells (RGCs), intermediate progenitors and outer RGCs. In addition, we detected robust MCT8 protein expression in deep layer and upper layer neurons. Spatiotemporal SLC16A2 mRNA expression, detected by fluorescent in situ hybridization (FISH), was highly concordant with MCT8 protein expression across cortical cell layers. FISH detected THRA mRNA expression already in neuroepithelium before the onset of neurogenesis. THRA mRNA expression remained low in the ventricular zone, increased in the subventricular zone whereas strong THRA expression was observed in excitatory neurons. In combination with a robust up-regulation of known T3 response genes following T3 treatment, these observations show that hCOs provide a promising and experimentally tractable model to probe local TH action during human cortical neurogenesis and eventually to model the consequences of impaired TH function for early cortex development.