Mathew Lijoy K, Andreasen Eric A, Tanguay Robert L
Department of Environmental and Molecular Toxicology, Marine and Freshwater Biomedical Sciences Center, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, USA.
Mol Pharmacol. 2006 Jan;69(1):257-65. doi: 10.1124/mol.105.018044. Epub 2005 Oct 7.
There is considerable literature supporting the conclusion that inappropriate activation of the aryl hydrocarbon receptor (AHR) alters cellular signaling. We have established previously that fin regeneration is specifically inhibited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in adult zebrafish and have used this in vivo endpoint to evaluate interactions between AHR and growth-controlling pathways. Because there are experimental limitations in studying regeneration in adult animals, we have developed a larval model to evaluate the effect of AHR activation on tissue regeneration. Two-day-old zebrafish regenerate their amputated caudal fins within 3 days. Here, we demonstrate that TCDD specifically blocks regenerative growth in larvae. The AHR pathway in zebrafish is considerably more complex than in mammals, with at least three zebrafish AHR genes (zfAHR1a, zfAHR1b, and zfAHR2) and two ARNT genes (zfARNT1 and zfARNT2). Although it was presumed that the block in regeneration was mediated by AHR activation, it had not been experimentally demonstrated. Using antisense morpholinos and mutant fish lines, we report that zfAHR2 and zfARNT1 are the in vivo dimerization partners that are required for inhibition of regeneration by TCDD. Several pathways including fibroblast growth factor (FGF) signaling are essential for fin regeneration. Even though impaired FGF signaling and TCDD exposure both inhibit fin regeneration, their morphometric response is distinct, suggesting that the mechanisms of impairment are different. With the plethora of molecular and genetic techniques that can be applied to larval-stage embryos, this in vivo regeneration system can be further exploited to understand cross-talk between AHR and other signaling pathways.
芳烃受体（AHR）的不适当激活会改变细胞信号传导。我们之前已经确定，在成年斑马鱼中，2,3,7,8-四氯二苯并对二恶英（TCDD）会特异性抑制鳍再生，并且我们已利用这一体内终点来评估AHR与生长控制途径之间的相互作用。由于在研究成年动物再生方面存在实验局限性，我们开发了一种幼体模型来评估AHR激活对组织再生的影响。两天大的斑马鱼在3天内就能再生其被截断的尾鳍。在此，我们证明TCDD会特异性阻断幼体的再生生长。斑马鱼中的AHR途径比哺乳动物中的要复杂得多，至少有三个斑马鱼AHR基因（zfAHR1a、zfAHR1b和zfAHR2）和两个ARNT基因（zfARNT1和zfARNT2）。尽管推测再生受阻是由AHR激活介导的，但尚未通过实验得到证实。利用反义吗啉代寡核苷酸和突变鱼系，我们报告zfAHR2和zfARNT1是TCDD抑制再生所需的体内二聚化伙伴。包括成纤维细胞生长因子（FGF）信号传导在内的几种途径对鳍再生至关重要。尽管FGF信号传导受损和TCDD暴露都会抑制鳍再生，但它们的形态计量学反应是不同的，这表明受损机制不同。由于有大量可应用于幼体阶段胚胎的分子和遗传技术，这个体内再生系统可以进一步用于了解AHR与其他信号通路之间的相互作用。
