Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α

Abstract

Genetic evidence from patients with mutations of the thyroid hormone receptor α gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRα1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TRα1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1 PV mice, expressing a dominant negative TRα1 mutant (TRα1PV), with mice expressing a mutant Ncor1 allele (Ncor1 ΔID mice) that cannot recruit the TR or PV mutant. TRα1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1ΔID ameliorated abnormalities in the thyroid-pituitary axis of Thra1 PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1 PV/+ mice expressing NCOR1ΔID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor γ and CCAAT/enhancerbinding protein α gene, due to the inability of TRα1PV to recruit NCOR1ΔID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TRα1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRα1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRα1 mutant-mediated hypothyroidism in patients.growth retardation | lipid metabolism | fertility defect T he thyroid hormone T3 regulates growth and development and maintains metabolic homeostasis in humans. The genomic signaling by T3 is via the thyroid hormone receptor (TR) isoforms α1, β1, and β2, which are encoded by the THRA and THRB genes located on two different chromosomes. These TR isoforms share extensive sequence homology in the DNA and T3 binding domains but differ in the amino terminal A/B domains (1). TR binds to the thyroid hormone response elements (TREs) and recruits nuclear coregulatory proteins to regulate gene transcription. In the absence of T3, TRs recruit the nuclear corepressors (NCOR1 and NCOR2) for transcriptional repression on the T3 positively regulated genes. In the presence of T3, the T3-bound TR undergoes structural changes, resulting in the release of corepressors, allowing recruitment of nuclear receptor coactivators (e.g., SRC-1) to facilitate transcription activation (2, 3).The critical roles of TR in mediating biological functions of T3 are clearly evident, in that mutations of the THRB gene cause resistance to thyroid hormone (RTH) (3). The intriguing observation that no mutations of the THRA gene were ever found in RTH patients raised the possibilities that mutations of the THRA gene could be embryonic lethal or could confer different clinical manifestations. These possibilities were explored by using a powerful mouse genetic approach. Targeting a ...

Thyroid Hormone Receptor Sumoylation Is Required for Preadipocyte Differentiation and Proliferation

“…Utilizing NCoR⌬ID to disrupt TR-NCoR interaction partially reversed the inhibition by the mutant TR, consistent with the mutation at Lys-443 influencing the interface with NCoR. A recent study reported that the altered adipogenesis seen in TR␣PV mice was completely rescued by expression of NCoR⌬ID (61). Although the model system and the TR mutation differ from the TR sumoylation mutants that we studied, the mechanism is similar.…”

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA)

“…The results from studies performed on mutant Thra mouse models suggest that the recruitment or action of coregulators, mainly corepressors, on TRα1 could be a target for treatment in individuals with THRA mutations 13. A better understanding of the role that TRα1 coregulator dysfunction plays in this genetic syndrome is necessary.…”

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

“…At peripheral level, weight loss, severe thyroid hyperplasia, and repression of a number of hepatic TR target genes were also reversed. Furthermore, expression of NCoRΔID could partially ameliorate abnormalities in the HPT axis of Thra1 PV/+ mice that carry the dominant-negative frameshift PV mutation and display a phenotype similar to that found in humans with mutations in Thra gene (Fozzatti et al 2013). NCoRΔID/Thra1 PV/+ animals also displayed improvement in severe growth retardation, infertility, delayed bone development, and impaired adipogenesis.…”