Thyroid hormones are important mediators of growth and development in vertebrates and act by binding to a specific family of thyroid receptors (TRs). The TRs belong to the nuclear receptor superfamily, with two conserved regions, a DNA binding domain and a ligand binding domain (LBD). We recently demonstrated the presence of four TR subtypes in goldfish, two with complete DNA binding domains and LBDs (TR␣-1 and TR␤) and two novel forms including a transcript resembling TR␣ with variation in the

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... LBD as well as a TR␣truncated (TR␣-t) form lacking a LBD. To study the functional significance of TR subtypes, we first investigated the regulation of hepatic goldfish deiodinase type 3 (D3) by T 3 and validated a bioassay in which D3 gene expression is up-regulated significantly in vivo and in vitro. Using short interfering RNA, TR␣-1, TR␤, or TR␣-t was specifically knocked down and thyroid hormone-induced D3 gene expression was measured. short interfering RNA against TR␣-1 or TR␤ reduced the T 3 induction of deiodinase gene expression to 50% or less than 25% of control (T 3 treated) cells, respectively. Knocking down TR␣-t alone, however, increased D3 expression 500-fold supporting the hypothesis that TR␣-t plays a modulatory role in thyroid hormone-induced gene expression. Our results provide important insight into thyroid receptor biology in goldfish and a framework for the better understanding of thyroid receptor function in all vertebrates. (Endocrinology 149: 4702-4709, 2008)