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

Tissue culture transfection and in vitro biochemical studies have sugg ested that heterodimers of thyroid hormone receptors (TRs) and 9-cis r etinoic acid receptors (RXRs) are the likely in vivo complexes that me diate the biological effects of thyroid hormone, 3,5,3'-triiodothyroni ne (T-3). However, direct in vivo evidence for such a hypothesis has b een lacking. We have previously reported a close correlation between t he coordinated expression of TR and RXR genes and tissue-dependent tem poral regulation of organ transformations during Xenopus laevis metamo rphosis. By introducing TRs and RXRs either individually or together i nto developing Xenopus embryos, we demonstrate here that RXRs are crit ical for the developmental function of TRs, Precocious expression of T Rs and RXRs together but not individually leads to drastic, distinct e mbryonic abnormalities, depending upon the presence or absence of T-3, 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 reg ulate endogenous T-3 response genes that are normally regulated by T-3 only during metamorphosis. That is, they repress the genes in the abs ence of T-3 and activate them in the presence of the hormone. On the o ther hand, the receptors have no effect on a retinoic acid (RA) respon se gene. Thus, RA- and T-3 receptor-mediated teratogenic effects in Xe nopus embryos occur through distinct molecular pathways, even though t he resulting phenotypes have similarities.