Publication Date:
2014-04-05
Description:
Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TRβ) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1 –/– mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 ( Ncor1 ) allele that cannot interact with TRβ, termed NCoRID, have low TH levels and normal TSH. We hypothesized that Src-1 –/– mice have RTH due to unopposed corepressor action. To test this, we crossed NCoRID and Src-1 –/– mice to create mice deficient for coregulator action in all cell types. Remarkably, NCoR ID/ID Src-1 –/– mice have normal TH and TSH levels and are triiodothryonine (T 3 ) sensitive at the level of the pituitary. Although absence of SRC-1 prevented T 3 activation of key hepatic gene targets, NCoR ID/ID Src-1 –/– mice reacquired hepatic T 3 sensitivity. Using in vivo chromatin immunoprecipitation assays (ChIP) for the related coactivator SRC-2, we found enhanced SRC-2 recruitment to TR-binding regions of genes in NCoR ID/ID Src-1 –/– mice, suggesting that SRC-2 is responsible for T 3 sensitivity in the absence of NCoR1 and SRC-1. Thus, T 3 targets require a critical balance between NCoR1 and SRC-1. Furthermore, replacement of NCoR1 with NCoRID corrects RTH in Src-1 –/– mice through increased SRC-2 recruitment to T 3 target genes.
Print ISSN:
0270-7306
Electronic ISSN:
1098-5549
Topics:
Biology
,
Medicine
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