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Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo
Nobuyuki Shibusawa, … , Ronald N. Cohen, Fredric E. Wondisford
Nobuyuki Shibusawa, … , Ronald N. Cohen, Fredric E. Wondisford
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):588-597. https://doi.org/10.1172/JCI18377.
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Article Endocrinology Article has an altmetric score of 1

Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo

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Abstract

Thyroid hormone action is mediated by thyroid hormone receptors (TRs), which are members of the nuclear hormone receptor superfamily. DNA-binding is presumed to be essential for all nuclear actions of thyroid hormone. To test this hypothesis in vivo, the DNA-binding domain of TR-β was mutated within its P-box (GS mutant) using gene targeting techniques. This mutation in vitro completely abolishes TR-β DNA-binding, while preserving ligand (T3) and cofactor interactions with the receptor. Homozygous mutant (TR-βGS/GS) mice displayed abnormal T3 regulation of the hypothalamic-pituitary-thyroid axis and retina identical to abnormalities previously observed in TR-β KO (TR-β–/–) mice. However, TR-βGS/GS mutant mice maintained normal hearing at certain frequencies and did not display significant outer hair cell loss, in contrast to TR-β–/– mice. DNA-binding, therefore, is essential for many functions of the TR, including retinal development and negative feedback regulation by thyroid hormone of the hypothalamic-pituitary-thyroid axis. Inner ear development, although not completely normal, can occur in the absence of TR DNA-binding, suggesting that an alternative and perhaps novel thyroid hormone-signaling pathway may mediate these effects.

Authors

Nobuyuki Shibusawa, Koshi Hashimoto, Amisra A. Nikrodhanond, M. Charles Liberman, Meredithe L. Applebury, Xiao Hui Liao, Janet T. Robbins, Samuel Refetoff, Ronald N. Cohen, Fredric E. Wondisford

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Figure 5

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Cochlear function and histopathology in TR-β mutant animals. (a) ABR thr...
Cochlear function and histopathology in TR-β mutant animals. (a) ABR thresholds for TR-βGS/GS and TR-β–/– mice are elevated with respect to TR-β+/+, but loss is greater in TR-β–/–. Data from individual 8-week-old animals are shown. (b) DPOAE thresholds for TR-βGS/GS and TR-β–/– mice are elevated with respect to WT; however, TR-β–/– exhibited a much greater deficit. Data are mean ± SEM. Group sizes were 10, 18, and 14 for TR-β+/+, TR-βGS/GS, and TR-β–/–, respectively. (c–e) Photomicrographs of the upper basal turn (cochlear frequency approximately 16 kHz) from WT and TR-β mutant cochleas. Arrows indicate: (c) tectorial membrane in TR-β+/+; (d) misaligned feet of outer pillar cells in TR-βGS/GS; (e) collapse of outer supporting cells (unfilled) and loss of spiral ligament fibrocytes in TR-β–/– (filled). Scale bar in c applies to all three images. (f–h) Basal-turn OHC loss is seen in TR-β–/– mice. Data from one ear of each genotype are shown. Symbol key in g applies to all three panels.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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