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Retinoid X receptor-selective ligands produce malformations in Xenopus embryos
S Minucci1, J P Saint-Jeannet, R Toyama
1Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Retinoids exert pleiotropic effects on the development of vertebrates through the action of retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the effect of synthetic retinoids selective for RXR and RAR on the development of Xenopus and zebrafish embryos. In Xenopus, both ligands selective for RAR and RXR caused striking malformations along the anterior-posterior axis, whereas in zebrafish only ligands specific for RAR caused embryonic malformations. In Xenopus, RAR- and RXR-selective ligands regulated the expression of the Xlim-1, gsc, and HoxA1 genes similarly as all-trans-retinoic acid. Nevertheless, RXR-selective ligands activated only an RXR responsive reporter but not an RAR responsive reporter introduced by microinjection into the Xenopus embryo, consistent with our failure to detect conversion of an RXR-selective ligand to different derivatives in the embryo. These results suggest that Xenopus embryos possess a unique response pathway in which liganded RXR can control gene expression. Our observations further illustrate the divergence in retinoid responsiveness between different vertebrate species.
Insights
Synthetic retinoids targeting retinoic acid receptors (RAR) and retinoid X receptors (RXR) reveal species-specific developmental effects. Xenopus embryos show unique RXR-dependent gene regulation, highlighting divergent retinoid pathways in vertebrates.
Area of Science:
- Developmental Biology
- Molecular Endocrinology
- Comparative Genomics
Background:
- Retinoids are crucial signaling molecules regulating vertebrate development.
- Retinoic acid receptors (RAR) and retinoid X receptors (RXR) mediate retinoid actions.
- Understanding retinoid pathway divergence across species is key to developmental research.
Purpose of the Study:
- To investigate the impact of RAR- and RXR-selective retinoids on Xenopus and zebrafish embryonic development.
- To elucidate the mechanisms of retinoid signaling in different vertebrate models.
- To identify species-specific differences in retinoid responsiveness.
Main Methods:
- Utilized synthetic retinoids selective for RAR and RXR.
- Examined embryonic malformations in Xenopus and zebrafish.
- Analyzed gene expression patterns (Xlim-1, gsc, HoxA1) using RT-PCR or similar techniques.
- Employed reporter gene assays in microinjected Xenopus embryos to assess receptor activation.
Main Results:
- RAR- and RXR-selective ligands induced anterior-posterior axis malformations in Xenopus.
- Only RAR-selective ligands caused malformations in zebrafish embryos.
- Both RAR- and RXR-selective ligands modulated Xlim-1, gsc, and HoxA1 gene expression in Xenopus.
- RXR-selective ligands activated RXR reporters but not RAR reporters in Xenopus, indicating direct RXR action.
Conclusions:
- Xenopus embryos exhibit a distinct retinoid response pathway involving direct RXR-mediated gene expression.
- Significant divergence in retinoid signaling pathways exists between Xenopus and zebrafish.
- These findings underscore the evolutionary plasticity of retinoid signaling in vertebrate development.