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Mol Cell Biol
1997 Aug 01;178:4738-49. doi: 10.1128/MCB.17.8.4738.
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Both thyroid hormone and 9-cis retinoic acid receptors are required to efficiently mediate the effects of thyroid hormone on embryonic development and specific gene regulation in Xenopus laevis.
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Tissue culture transfection and in vitro biochemical studies have suggested that heterodimers of thyroid hormone receptors (TRs) and 9-cis retinoic acid receptors (RXRs) are the likely in vivo complexes that mediate the biological effects of thyroid hormone, 3,5,3'-triiodothyronine (T3). However, direct in vivo evidence for such a hypothesis has been lacking. We have previously reported a close correlation between the coordinated expression of TR and RXR genes and tissue-dependent temporal regulation of organ transformations during Xenopus laevis metamorphosis. By introducing TRs and RXRs either individually or together into developing Xenopus embryos, we demonstrate here that RXRs are critical for the developmental function of TRs. Precocious expression of TRs and RXRs together but not individually leads to drastic, distinct embryonic abnormalities, depending upon the presence or absence of T3, and these developmental effects require the same receptor domains as those required for transcriptional regulation by TR-RXR heterodimers. More importantly, the overexpressed TR-RXR heterodimers faithfully regulate endogenous T3 response genes that are normally regulated by T3 only during metamorphosis. That is, they repress the genes in the absence of T3 and activate them in the presence of the hormone. On the other hand, the receptors have no effect on a retinoic acid (RA) response gene. Thus, RA- and T3 receptor-mediated teratogenic effects in Xenopus embryos occur through distinct molecular pathways, even though the resulting phenotypes have similarities.
FIG. 2. Overexpression of TRs and RXRs together results in dose- and T3-dependent embryonic abnormalities. Embryos were injected with the indicated amounts of TR-RXR mRNAs and cultured for 2 days in the presence (ﰂ) or absence (ﲎ) of 100 nM T3.
FIG. 7. Phenotypic analyses of the embryos injected with wild-type and mutant receptor mRNAs reveal that the requirements for receptor function in embryo- genesis and transcriptional regulation in oocytes are identical. The embryos injected with indicated mRNAs were cultured in the presence (B, D, F, and H) or absence (A, C, E, and G) of T3, and their phenotypes were examined after 48 h. Comparisons of TRalphaA and TRbetaA (A and B), TRalphaA and and TBetaADeltaAF2 (C and D), TRalpha and TRalphaADeltaDBD (E and F), and RXRaplha and RXRalphaDeltaAF2 (G and H) are shown. Note that the phenotypes of embryos with over-expressed TRBetaalphaAF2-RXR in the presence of T3 were identical to those in the absence of T3.
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