Thra, short for thyroid hormone receptor α, encodes the thyroid hormone nuclear receptor TRα1. Thyroid hormone action is predominantly mediated by thyroid hormone receptors encoded by Thra and Thrb genes. Thra is involved in multiple biological processes, including bone remodeling, nervous system development, and is associated with pathways like Wnt and Notch, playing a crucial role in maintaining normal physiological functions [2,3,4].

In intestinal lesions, Thra is upregulated in colorectal cancers, especially in the high-Wnt molecular subtype. Transcription factors such as TCF7L2 (Wnt pathway), RBPJ (Notch pathway), and CDX2 modulate Thra activity, unveiling a complex regulatory loop between endocrine and epithelial-cell-intrinsic signals [1]. In osteoblasts, Thra knockout promoted the differentiation and activity of early, mature, and late osteoblasts, while Thrb knockout mitigated the responsiveness of osteoblasts to thyroid hormone treatment, emphasizing Thra's role in bone-related thyroid hormone actions [3]. In human cerebral organoids, Thra mRNA is expressed in neuroepithelium before neurogenesis, with its expression increasing in the subventricular zone and being strong in excitatory neurons, indicating its importance in early brain development [4].

In conclusion, Thra is essential for normal physiological functions, especially in processes like bone development, intestinal homeostasis, and early brain development. Gene knockout models, like in mice, have been crucial in revealing its role in these processes and associated disease conditions such as colorectal cancer, highlighting its significance in understanding disease mechanisms [1,3,4].

References:

1. Giolito, Maria Virginia, La Rosa, Théo, Farhat, Diana, Freund, Jean-Noel, Plateroti, Michelina. 2022. Regulation of the THRA gene, encoding the thyroid hormone nuclear receptor TRα1, in intestinal lesions. In Molecular oncology, 16, 3975-3993. doi:10.1002/1878-0261.13298. https://pubmed.ncbi.nlm.nih.gov/36217307/

2. Ortiga-Carvalho, Tânia M, Sidhaye, Aniket R, Wondisford, Fredric E. 2014. Thyroid hormone receptors and resistance to thyroid hormone disorders. In Nature reviews. Endocrinology, 10, 582-91. doi:10.1038/nrendo.2014.143. https://pubmed.ncbi.nlm.nih.gov/25135573/

3. Lademann, Franziska, Tsourdi, Elena, Hofbauer, Lorenz C, Rauner, Martina. 2023. Thyroid hormone receptor Thra and Thrb knockout differentially affects osteoblast biology and thyroid hormone responsiveness in vitro. In Journal of cellular biochemistry, 124, 1948-1960. doi:10.1002/jcb.30500. https://pubmed.ncbi.nlm.nih.gov/37992217/

4. Graffunder, Adina Sophie, Bresser, Audrey Amber Julie, Fernandez Vallone, Valeria, Kühnen, Peter, Opitz, Robert. 2024. Spatiotemporal expression of thyroid hormone transporter MCT8 and THRA mRNA in human cerebral organoids recapitulating first trimester cortex development. In Scientific reports, 14, 9355. doi:10.1038/s41598-024-59533-2. https://pubmed.ncbi.nlm.nih.gov/38654093/