title: Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo.
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-beta was mutated within its P-box (GS mutant) using gene targeting techniques. This mutation in vitro completely abolishes TR-beta DNA-binding, while preserving ligand (T3) and cofactor interactions with the receptor. Homozygous mutant (TR-betaGS/GS) mice displayed abnormal T3 regulation of the hypothalamic-pituitary-thyroid axis and retina identical to abnormalities previously observed in TR-beta KO (TR-beta-/-) mice. However, TR-betaGS/GS mutant mice maintained normal hearing at certain frequencies and did not display significant outer hair cell loss, in contrast to TR-beta-/- 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.affiliation: Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, MC1027, Chicago, Illinois 60637, USA.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shibusawa
authors.forename: Koshi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Amisra A
authors.initials: AA
authors.lastname: Nikrodhanond
authors.forename: M Charles
authors.initials: MC
authors.lastname: Liberman
authors.forename: Meredithe L
authors.initials: ML
authors.lastname: Applebury
authors.forename: Xiao Hui
authors.initials: XH
authors.lastname: Liao
authors.forename: Janet T
authors.initials: JT
authors.lastname: Robbins
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cohen
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D018776:Genes, erbA / Q000235:genetics; D006720:Homozygote; D007150:Immunohistochemistry; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D013963:Thyroid Hormones / Q000097:blood / Q000378:metabolism*; D013997:Time Factors
chemical_list: D008024:Ligands; D013963:Thyroid Hormones; D004247:DNA