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

Background: Thyroid hormone receptors TR alpha 1, TR beta 1 and TR beta 2 are broadly expressed and exert a pleiotropic influence on many developmental and homeostatic processes. Extensive genetic studies in mice precisely defined their respective function. Scope of review: The purpose of the review is to discuss two puzzling issues: The isoforrn specificity problem: the different functions of TR alpha 1, TR beta 1 and TR beta 2 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. Major conclusions: 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. General significance: 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. (C) 2012 Elsevier B.V. All rights reserved.