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

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

Research output: Contribution to journalArticle

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 (T 3) 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.

Original languageEnglish (US)
Pages (from-to)588-597
Number of pages10
JournalJournal of Clinical Investigation
Volume112
Issue number4
DOIs
StatePublished - Aug 2003
Externally publishedYes

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Thyroid Hormone Receptors
Thyroid Hormones
DNA
Outer Auditory Hair Cells
Thyroid Gland
Gene Targeting
Alopecia
Inner Ear
Cytoplasmic and Nuclear Receptors
Hearing
Retina
Ligands
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shibusawa, N., Hashimoto, K., Nikrodhanond, A. A., Liberman, M. C., Applebury, M. L., Liao, X. H., ... Wondisford, F. E. (2003). Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo. Journal of Clinical Investigation, 112(4), 588-597. https://doi.org/10.1172/JCI200318377

Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo. / Shibusawa, Nobuyuki; Hashimoto, Koshi; Nikrodhanond, Amisra A.; Liberman, M. Charles; Applebury, Meredithe L.; Liao, Xiao Hui; Robbins, Janet Liao T; Refetoff, Samuel; Cohen, Ronald N.; Wondisford, Fredric E.

In: Journal of Clinical Investigation, Vol. 112, No. 4, 08.2003, p. 588-597.

Research output: Contribution to journalArticle

Shibusawa, N, Hashimoto, K, Nikrodhanond, AA, Liberman, MC, Applebury, ML, Liao, XH, Robbins, JLT, Refetoff, S, Cohen, RN & Wondisford, FE 2003, 'Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo', Journal of Clinical Investigation, vol. 112, no. 4, pp. 588-597. https://doi.org/10.1172/JCI200318377
Shibusawa N, Hashimoto K, Nikrodhanond AA, Liberman MC, Applebury ML, Liao XH et al. Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo. Journal of Clinical Investigation. 2003 Aug;112(4):588-597. https://doi.org/10.1172/JCI200318377
Shibusawa, Nobuyuki ; Hashimoto, Koshi ; Nikrodhanond, Amisra A. ; Liberman, M. Charles ; Applebury, Meredithe L. ; Liao, Xiao Hui ; Robbins, Janet Liao T ; Refetoff, Samuel ; Cohen, Ronald N. ; Wondisford, Fredric E. / Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo. In: Journal of Clinical Investigation. 2003 ; Vol. 112, No. 4. pp. 588-597.
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