Marked potentiation of the dominant negative action of a mutant thyroid hormone receptor beta in mice by the ablation of one wild-type beta allele.
Mutations in the thyroid hormone receptor (TR) beta gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRbeta mutation (TRbetaPV) with mice carrying a TRbeta null mutation (TRbeta(-/-)) to determine the consequences of the TRbetaPV mutation in the absence of wild-type TRbeta. TRbeta(PV/-) mice are distinct from TRbeta(+/-) mice that did not show abnormalities in thyroid function tests. TRbeta(PV/-) mice are also distinct from TRbeta(PV/+) and TRbeta(-/-) mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRbeta(PV/PV) mice. Similar to TRbeta(PV/PV) mice, TRbeta(PV/-) mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T3-target genes in the tissues of TRbeta(PV/-) and TRbeta(PV/PV) mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TRalpha1 for binding to thyroid hormone response elements in TRbeta(PV/-) mice as effectively as in TRbeta(PV/PV) mice. Thus, the actions of mutant TRbeta are markedly potentiated by the ablation of the second TRbeta allele, suggesting that interference with wild-type TRalpha1-mediated gene regulation by mutant TRbeta leads to severe RTH.
Suzuki
H
H
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892-4264, USA.
Zhang
X-Y
XY
Forrest
D
D
Willingham
M C
MC
Cheng
S-Y
SY
D000483:Alleles; D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006965:Hyperplasia / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010902:Pituitary Gland / Q000503:physiopathology; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013961:Thyroid Gland / Q000503:physiopathology; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics; D013972:Thyrotropin / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism; D015430:Weight Gain / Q000235:genetics
D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013972:Thyrotropin