Retinoid-X receptors: signaling hubs and novel targets of endocrine disruption

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Abstract The centrality of RXR to nuclear receptor signaling—over a third of NRs heterodimerize with an RXR—suggest that endocrine disruption of RXR signaling could affect the myriad gene expression programs mediated by these receptors, resulting in adverse developmental and metabolic outcomes. We became interested in RXR disruption when RXR agonists surprisingly arose as positive hits in a high throughput quantitative screen we developed for thyroid hormone (TH) receptor (TR) signaling. TRs heterodimerize with RXRs, but in those heterodimers the RXR is thought to be a “silent” partner, meaning that RXR ligands will not affect the activity of the heterodimer. In rats and humans, prior evidence has shown that Vitamin A or pharmacological rexinoids like bexarotene can effect TH homeostasis in adults. Therefore, the role of RXR agonists in TR transcriptional regulation remains unclear, and the mechanisms through which RXR regulates TH signaling remain a major gap in our understanding. Our hypothesis is that endocrine disruption of RXR can affect TH signaling through TRs during development, creating unforeseen adverse consequences. This may be especially true when the HPT axis is not yet functional or not operating due to TH supplementation. In this proposal we will examine the effects of pharmaceutical and environmental RXR agonists and antagonists on a well-defined in vivo model of TH action: precocious Xenopus metamorphosis. We will define and compare the gene expression programs that RXR disruption affects. In addition, we will use precise genome editing to genetically interrogate the roles of specific RXR subtypes in an intact organism, along with using those editing tools to tag the different RXR and TR subtypes for downstream expression analyses during development. In summary, the Xenopus system is an accessible, rapid and relatively cost efficient means of examining the role of normal and environmental ligand modulated RXR in TR actions in vivo, including both biomedical and environmental toxicological implications in cell-fate specific and developmental stage specific platforms.