Multiple isoforms of thyroid hormone receptor: an analysis of their relative contribution in mediating thyroid hormone action.

Thyroid hormone is essential for normal development and maintaining metabolic homeostasis. In mediating the thyroid hormone action, the thyroid hormone receptor (TR) plays a key role. Almost one decade ago, the cloning of TR was achieved, revealing the existence of at least two genes, TR alpha and TR beta, which encode TR. From these genes several TR isoforms can be generated by alternative splicing. They are designated as TR alpha 1, TR alpha 2 (inactive form), TR beta 1 and TR beta 2. Since the discovery of these TR isoforms, many studies have attempted to demonstrate their relative contribution to mediate thyroid hormone in various tissues. The distinct tissue distribution and the ontogenic expression of the TR isoforms, and the fact that TR gene abnormalities associated with the syndrome of resistance to thyroid hormone (RTH) have been found only in the TR beta gene, indicate that products of TR alpha and TR beta have distinct roles. However, no direct evidence of the distinct roles of the TR isoforms has been shown. Gene knockouts of either TR isoform would provide important information to understanding their specific roles. In this review, the history of the TR isoform discovery and studies attempting to demonstrate the specific roles of TR isoforms are summarized, and recent reports dealing with knockouts of TR isoforms are comprehensively presented.