Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo.
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.
Shibusawa
Nobuyuki
N
Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, MC1027, Chicago, Illinois 60637, USA.
Hashimoto
Koshi
K
Nikrodhanond
Amisra A
AA
Liberman
M Charles
MC
Applebury
Meredithe L
ML
Liao
Xiao Hui
XH
Robbins
Janet T
JT
Refetoff
Samuel
S
Cohen
Ronald N
RN
Wondisford
Fredric E
FE
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
D008024:Ligands; D013963:Thyroid Hormones; D004247:DNA