The molecular genetic basis of thyroid carcinogenesis is not well understood. Most of the existing models of thyroid cancer only rarely show metastases, and this has limited progress in the understanding of the molecular events in thyroid cancer invasion and metastasis. We have recently generated a mutant mouse by introducing a dominant negative mutant thyroid hormone nuclear receptor gene, TRbetaPV, into the TRbeta gene locus. In this TRbetaPV mouse, the regulation of the thyroid-pituitary axis is disrupted, leading to a mouse with high levels of circulating thyroid-stimulating hormone and extensive hyperplasia of follicular epithelium within the thyroid. As TRbeta(PV/PV) mice, but not TRbeta(PV/+) mice, aged, metastatic thyroid carcinoma developed. Histologic evaluation of thyroids of 5-14-month-old mice showed capsular invasion (91%), vascular invasion (74%), anaplasia (35%), and metastasis to the lung and heart (30%). Previous models of thyroid cancer have focused on genes that control initial carcinogenesis, but this model provides an unusual opportunity to study the alterations in gene regulation that occur with clinically relevant changes during progression and metastasis in a predictable fashion.
Mutations in the thyroid hormone receptor  (TR) gene result in resistance to thyroid hormone. However, it is unknown whether mutations in the TR␣ gene could lead to a similar disease. To address this question, we prepared mutant mice by targeting mutant thyroid hormone receptor kindred PV (PV) mutation to the TR␣ gene locus by means of homologous recombination (TR␣1PV mice). The PV mutation was derived from a patient with severe resistance to thyroid hormone that has a frameshift of the C-terminal 14 aa of TR1. We knocked in the same PV mutation to the corresponding TR␣ gene locus to compare the phenotypes of TR␣1 PV/؉ mice with those of TR PV/؉ mice. TR␣1 PV/؉ mice were viable, indicating that the mutation of the TR␣ gene is not embryonic lethal. In drastic contrast to the TR PV/؉ mice, which do not exhibit a growth abnormality, TR␣1 PV/؉ mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TR PV/؉ mice, which have a hyperactive thyroid, TR␣1 PV/؉ mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TR␣1 PV/؉ mice was unique from those of TR PV/؉ mice. The distinct phenotypes exhibited by TR␣1 PV/؉ and TR PV/؉ mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TR␣1 PV/؉ mice may be used as a tool to uncover human diseases associated with mutations in the TR␣ gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities.T he thyroid hormone, T3, has profound effects on growth, development, and homeostasis. These biological activities are mediated mainly by thyroid hormone receptors (TRs) that are ligand-dependent transcription factors (1). Three ligand-binding TR isoforms have been identified, TR␣1, TR1, and TR2, which are derived from the TR␣ and TR genes, by alternative splicing of the primary transcripts. Each TR isoform has a unique developmental and tissue-specific expression (1, 2). Studies using a geneinactivation approach indicate that these TR isoforms have distinct and common functions in vivo (3). The action of TR depends not only on the types of DNA elements on the T3 target genes but also on a host of corepressor and coactivator proteins (1, 2).Resistance to thyroid hormone (RTH) is a syndrome characterized by reduction in the sensitivity of tissues to the action of thyroid hormones. Mutations in the TR gene result in TR mutants, which mediate the clinical phenotype by interfering with transcription of T3-regulated genes by means of a dominant negative effect. This disease is manifested by elevated levels of circulating thyroid hormones associated with normal or high levels of serum thyroidstimulating hormone (TSH) (4). The other clinical features include short stature, decreased weight, tachycardia, cardiac disease and hearing loss, attention-deficit hyperactivity disorder, decreased IQ, and dyslexia (4). Based on the extensive sequence homology in the functional domains of ␣ and  TR and their similar in vi...
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