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

摘要 RXR对核受体信号传导的中心作用--超过三分之一的核受体与RXR异源二聚化--表明 RXR信号的内分泌干扰可能会影响由RXR介导的无数基因表达程序。 这些受体，导致不利的发育和代谢结果。我们对RXR产生了兴趣 当RXR激动剂在高通量定量筛选中意外地作为阳性命中出现时， 甲状腺激素（TH）受体（TR）信号转导。TR与RXR异二聚化，但在那些 RXR被认为是一种“沉默”伴侣，这意味着RXR配体不会影响异二聚体的活性。 异二聚体。在大鼠和人类中，先前的证据表明，维生素A或药理学rexinoids 像贝沙罗汀可以影响成人的TH稳态。因此，RXR激动剂在TR转录调控中的作用可能与其在转录调控中的作用有关。 调节仍然不清楚，RXR调节TH信号的机制仍然是一个主要的问题。 我们理解的差距。我们的假设是，RXR的内分泌干扰可以通过以下途径影响TH信号传导： 开发过程中的TR，造成不可预见的不良后果。这可能是特别真实的时候， HPT轴尚未发挥功能或由于TH补充而不工作。在本建议中，我们将审查 药物和环境RXR激动剂和拮抗剂对明确定义的体内模型的影响 TH作用：早熟的非洲爪蟾变态。我们将定义和比较基因表达程序 RXR干扰的影响。此外，我们将使用精确的基因组编辑来从基因上询问这些角色， 沿着使用这些编辑工具来标记不同的RXR亚型， 和TR亚型用于发育过程中的下游表达分析。总之，Xenopus系统 是一种方便、快捷和相对具有成本效益的手段，可以检查正常和环境的作用， 配体调节的RXR在体内TR作用，包括生物医学和环境毒理学 在细胞命运特异性和发育阶段特异性平台中的意义。

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.