1. Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1)Mutations in the ligand-binding domain of TRbeta lead to resistance to thyroid hormone (RTH). These TRbeta mutants function in a dominant negative fashion to interfere with the transcription activity of wild-type TRs, leading to dys-regulation of the pituitary-thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TRbeta mutants cause RTH has been postulated to be an inability of the mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone TRbetaPV mice that is a model of RTH, expressing a human TRbeta mutant (PV), with mice expressing a mutant Ncor1 allele (Ncor1deltaID mice) that cannot recruit TR or PV mutant. Remarkably, in the presence of NCOR1deltaID, the abnormally elevated TSH and TH levels found in TRbetaPV mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH, were also partially reverted in mice expressing NCOR1deltaID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRbeta mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR-NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH.2. Activation of Wnt/beta-catenin signaling in the skeleton of mice with advanced bone formation due to a dominant-negative mutation in the thyroid hormone receptor beta geneThyroid hormone (T3) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance but the signaling pathways mediating these effects are poorly understood. TRbetaPV/PV mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant-negative mutant TRbeta (TRbetaPV) that cannot bind T3 and interferes with the actions of wild-type TR. TRbetaPV/PV mice have accelerated skeletal development due to unknown mechanisms. We performed microarray studies in primary osteoblasts from wild-type mice and TRbetaPV/PV mice. Activation of the canonical Wnt signaling in TRbetaPV/PV mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during post-natal growth. By contrast, T3 treatment increased phosphorylation of beta-catenin and inhibited Wnt signaling in osteoblastic cells, indicating T3 inhibits the Wnt pathway by facilitating proteasomal degradation of beta-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in TRbetaPV/PV mice, however, suggests a gain-of-function for TRbetaPV that stabilizes beta-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions between T3 and Wnt signaling pathways in the regulation of skeletal development and bone formation.