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Molecular Endocrinology 15 (3): 467-475
Copyright © 2001 by The Endocrine Society

Distinct Tissue-Specific Roles for Thyroid Hormone Receptors ß and {alpha}1 in Regulation of Type 1 Deiodinase Expression

Lori L. Amma, Angel Campos-Barros, Zhendong Wang, Björn Vennström and Douglas Forrest

Department of Human Genetics (L.L.A., A.C.-B., Z.W., D.F.) Mount Sinai School of Medicine New York, New York 10029
Laboratory of Developmental Biology (B.V.) CMB, Karolinska Institute Stockholm, S-17 177, Sweden

Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to control levels of T3, the active ligand for thyroid hormone receptors (TR). The D1 gene is itself T3-inducible and here, the regulation of D1 expression by TR{alpha}1 and TRß, which act as T3-dependent transcription factors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TRß-/- but not TR{alpha}1-/- mice. Liver D1 remained weakly T3 inducible in TRß–/– mice whereas induction was abolished in double mutant TR{alpha}1–/–TRß–/– mice. This indicates that TRß is primarily responsible for regulating D1 expression whereas TR{alpha}1 has only a minor role. In kidney, despite the expression of both TR{alpha}1 and TRß, regulation relied solely on TRß, thus revealing a marked tissue restriction in TR isotype utilization. Although TRß and TR{alpha}1 mediate similar functions in vitro, these results demonstrate differential roles in regulating D1 expression in vivo and suggest that tissue-specific factors and structural distinctions between TR isotypes contribute to functional specificity. Remarkably, there was an obligatory requirement for a TR, whether TRß or TR{alpha}1, for any detectable D1 expression in liver. This suggests a novel paradigm of gene regulation in which the TR sets both basal expression and the spectrum of induced states. Physiologically, these findings suggest a critical role for TRß in regulating the thyroid hormone status through D1-mediated metabolism.




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