Thyroid hormone receptors: The challenge of elucidating isotype-specific functions and cell-specific response

• Published in: Biochimica et biophysica acta Vol. 1830; no. 7; pp. 3900 - 3907
• Main Authors: Flamant, Frédéric, Gauthier, Karine
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2013
• Subjects: Animals; drugs; endocrine-disrupting chemicals; genetics; Humans; mice; Mouse genetics; Nuclear receptor; Protein Isoforms; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - metabolism; Receptors, Thyroid Hormone - physiology; Signal Transduction; Thyroid hormone; thyroid hormone receptors; thyroid hormones; Thyroid Hormones - genetics; Thyroid Hormones - metabolism; Thyroid hormone; Nuclear receptor; Mouse genetics
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.06.003

Thyroid hormone receptors TRα1, TRβ1 and TRβ2 are broadly expressed and exert a pleiotropic influence on many developmental and homeostatic processes. Extensive genetic studies in mice precisely defined their respective function. The purpose of the review is to discuss two puzzling issues:–The isoform specificity problem: the different functions of TRα1, TRβ1 and TRβ2 might reflect either their different distribution in tissues or differences in the receptor intrinsic properties.–The cell-specificity problem: one would expect that different cell types share a common repertoire of TR target genes, but current knowledge does not support this assumption. How TR function is affected by the cellular context is an unsolved question. Mouse genetics support a balanced contribution of expression pattern and receptor intrinsic properties in defining the receptor respective functions. The molecular mechanisms sustaining cell specific response remain hypothetical and based on studies performed with other nuclear receptors. The isoform-specificity and cell-specificity questions have many implications for clinical research, drug development, and endocrine disruptor studies. This article is part of a Special Issue entitled Thyroid hormone signalling. ► Genetic data indicate different functions for thyroid hormone receptor isotypes. ► Combination of knock-out suggest functional redundancy between the isotypes. ► Isotype specific functions exist in some cell types. ► Thyroid hormone target genes differ, depending on cell type and species. ► Synthetic ligands and environmental pollutants modify thyroid hormone signaling.