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 
TRalpha1 and TRbeta, which act as T3-dependent transcription factors, was 
investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity 
levels were reduced in TRbeta(-/-) but not TRalpha1(-/-) mice. Liver D1 remained 
weakly T3 inducible in TRbeta(-/-) mice whereas induction was abolished in 
double mutant TRalpha1(-/-)TRbeta(-/-) mice. This indicates that TRbeta is 
primarily responsible for regulating D1 expression whereas TRalpha1 has only a 
minor role. In kidney, despite the expression of both TRalpha1 and TRbeta, 
regulation relied solely on TRbeta, thus revealing a marked tissue restriction 
in TR isotype utilization. Although TRbeta and TRalpha1 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 TRbeta or 
TRalpha1, 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 TRbeta in regulating the thyroid hormone status through D1-mediated 
metabolism.