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The administration of the teratogen retinoic acid (and other retinoids) to vertebrate embryos causes a range of developmental abnormalities. It remains to be shown how these teratogenic effects are mediated, and whether or not they reflect any morphogenetic roles retinoids may have in normal development. The most intensively studied cellular action of retinoids has been the activation of retinoid receptors (RARs and RXRs), which are members of the steroid/thyroid family of ligand-modulated transcription factors. Here we report experiments designed to investigate whether the teratogenic effects of retinoic acid on early Xenopus embryos are mediated transcriptionally by receptors, and if these receptors are necessary for normal early Xenopus development. We have demonstrated transcriptional activation of injected reporter genes by exogeneously supplied retinoic acid in Xenopus embryos, presumably as a consequence of the activation of endogenous retinoid receptors. This assay system has been used to demonstrate functional expression, from injected mRNA of (1) a wild-type RARγ (2) a domain-swapped receptor in which the retinoic acid binding domain has been replaced by a thyroid hormone domain to create a thyroid hormone responsive receptor, and (3) a dominant negative from of the RARγ. The wild-type RARγ increases the severity of retinoic acid-mediated defects. In the presence of thyroid hormone the domain-swapped receptor causes abnormalities of gastrulation. The dominant negative decreases the severity of retinoic acid-mediated defects. We conclude that the teratogenic effects of exogenous retinoic acid on Xenopus embryos are mediated, at least in part, transcriptionally via retinoid receptors. It is notable that the dominant negative has no effect on normal development in the absence of exogenous retinoic acid. This is despite observations that this receptor completely blocks transcriptional activation of reporter genes by exogenous retinoic acid up to the beginning of gastrulation, and substantially relieves the teratogenic effects of retinoic acid.
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