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Functional Significance of a Truncated Thyroid Receptor Subtype Lacking a Hormone-Binding Domain in Goldfish

Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada T2N 1N4

Address all correspondence and requests for reprints to: Hamid R. Habibi, Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4. E-mail: habibi{at}ucalgary.ca.

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 TRβ) and two novel forms including a transcript resembling TR with variation in the 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 T₃ and validated a bioassay in which D3 gene expression is up-regulated significantly in vivo and in vitro. Using short interfering RNA, TR-1, TRβ, or TR-t was specifically knocked down and thyroid hormone-induced D3 gene expression was measured. short interfering RNA against TR-1 or TRβ reduced the T₃ induction of deiodinase gene expression to 50% or less than 25% of control (T₃ 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.