Isoform-dependent actions of thyroid hormone nuclear receptors: Lessons from knockin mutant mice

Thyroid hormone nuclear receptors (TRs) mediate the biological activities of the thyroid hormone (T3) in growth, development and differentiation and in the maintenance of metabolic homeostasis. They are derived from two separate genes to yield four major T3-binding isoforms: α1, β1, β2, and β3. To understand whether TR isoforms mediate specific functions in vivo, PV mutation, identified from a patient with resistance to thyroid hormone (RTH), was targeted to the TRβ (TRβPV mice) or TRα gene (TRα1PV mice). PV has a frame-shift mutation in the last 14 carboxyl-terminal amino acids of TRβ1 or TRα1, resulting in the loss of T3-binding and transcriptional activities. TRβPV mice faithfully reproduce human RTH with dysfunction of the pituitary-thyroid axis, impairment in weight gain and accelerated bone development, hearing defects, abnormal regulation of serum cholesterol and increased physical activity reminiscent of attention deficit-hyperactivity disorder. In contrast, TRα1PV mice show no abnormalities in the pituitary-thyroid axis and other discernable RTH phenotypes. In addition, TRα1PV mice are dwarfs with high mortality, reduced fertility and survival, reduced glucose utilization in the brain and marked delay in bone development. These results clearly show that the molecular actions of TRα1PV are distinct from those of TRβPV in vivo. Further studies indicate that these contrasting phenotypes are mediated by distinct isoform-dependent abnormal regulation of T3-target genes in tissues. Thus, these two mutant mice provide a valuable tool for further dissecting the molecular bases of isoform-dependent actions of mutant TRs in vivo and their roles in disease.