Walisser Jacqueline A, Bunger Maureen K, Glover Edward, Bradfield Christopher A
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16677-82. doi: 10.1073/pnas.0404379101. Epub 2004 Nov 15.
The aryl hydrocarbon receptor (AHR) is commonly known for its role in the adaptive metabolism of xenobiotics and in the toxic events that follow exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Previously, we have demonstrated that the AHR and its heterodimeric partner, the AHR nuclear translocator (ARNT), play a role in the developmental closure of a hepatic vascular shunt known as the ductus venosus (DV). To investigate the mechanism of DV closure, we generated hypomorphic alleles of the Ahr and Arnt loci. Using these models, we then asked whether this vascular defect could be rescued by receptor activation during late development. By manipulating gestational exposure, the patent DV in AHR or ARNT hypomorphs could be efficiently closed by dioxin exposure as early as embryonic day 12.5 and as late as embryonic day 18.5. These findings define the temporal regulation of receptor activation during normal ontogeny and provide evidence to support the idea that receptor activation and AHR-ARNT heterodimerization are essential for normal vascular development. Taken in the broader context, these data demonstrate that similar AHR signaling steps govern all major aspects of AHR biology.
芳烃受体（AHR）因其在异生素的适应性代谢以及接触2,3,7,8-四氯二苯并对二恶英（二恶英）后发生的毒性事件中的作用而广为人知。此前，我们已经证明AHR及其异二聚体伴侣——AHR核转运蛋白（ARNT），在一种称为静脉导管（DV）的肝血管分流的发育性闭合中发挥作用。为了研究DV闭合的机制，我们构建了Ahr和Arnt基因座的低表达等位基因。利用这些模型，我们接着探究这种血管缺陷是否能在发育后期通过受体激活得到挽救。通过控制孕期暴露，早在胚胎第12.5天以及晚至胚胎第18.5天，二恶英暴露就能有效闭合AHR或ARNT低表达小鼠的开放DV。这些发现确定了正常个体发育过程中受体激活的时间调控，并为支持受体激活和AHR-ARNT异二聚化对正常血管发育至关重要这一观点提供了证据。从更广泛的背景来看，这些数据表明类似的AHR信号传导步骤控制着AHR生物学的所有主要方面。
