Multi-tissue gene-expression analysis in a mouse model of thyroid hormone resistance

Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor beta (TRbeta) gene. To understand the transcriptional program underlying TRbeta mutant-induced phenotypic expression of RTH, cDNA microarrays were used to profile the expression of 11,500 genes in a mouse model of human RTH.

We analyzed transcript levels in cerebellum, heart and white adipose tissue from a knock-in mouse (TRbetaPV/PV mouse) that harbors a human mutation (referred to as PV) and faithfully reproduces human RTH. Because TRbetaPV/PV mice have elevated thyroid hormone (T3), to define T3-responsive genes in the context of normal TRbeta, we also analyzed T3 effects in hyperthyroid wild-type gender-matched littermates. Microarray analysis revealed 163 genes responsive to T3 treatment and 187 genes differentially expressed between TRbetaPV/PV mice and wild-type littermates. Both the magnitude and gene make-up of the transcriptional response varied widely across tissues and conditions. We identified genes modulated in T3-dependent PV-independent, T3- and PV-dependent, and T3-independent PV-dependent pathways that illuminated the biological consequences of PV action in vivo. Most T3-responsive genes that were dysregulated in the heart and white adipose tissue of TRbetaPV/PV mice were repressed in T3-treated wild-type mice and upregulated in TRbetaPV/PV mice, suggesting the inappropriate activation of T3-suppressed genes in RTH.

Comprehensive multi-tissue gene-expression analysis uncovered complex multiple signaling pathways that mediate the molecular actions of TRbeta mutants in vivo. In particular, the T3-independent mutant-dependent genomic response unveiled the contribution of a novel 'change-of-function' of TRbeta mutants to the pathogenesis of RTH. Thus, the molecular actions of TRbeta mutants are more complex than previously envisioned.