Garland Michael A, Sengupta Sumitra, Mathew Lijoy K, Truong Lisa, de Jong Esther, Piersma Aldert H, La Du Jane, Tanguay Robert L
Department of Environmental and Molecular Toxicology, United States.
Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
Toxicol Rep. 2019 May 29;6:529-537. doi: 10.1016/j.toxrep.2019.05.013. eCollection 2019.
We previously used a chemical genetics approach with the larval zebrafish to identify small molecule inhibitors of tissue regeneration. This led to the discovery that glucocorticoids (GC) block early stages of tissue regeneration by the inappropriate activation of the glucocorticoid receptor (GR). We performed a microarray analysis to identify the changes in gene expression associated with beclomethasone dipropionate (BDP) exposure during epimorphic fin regeneration. Oncofetal showed > eight-fold increased expression in BDP-treated regenerates. We hypothesized that the mis-expression of was essential for BDP to block regeneration. Expression of was not elevated in GR morphants in the presence of BDP indicating that induction was GR-dependent. Partial translational suppression of Cripto-1 in the presence of BDP restored tissue regeneration. Retinoic acid exposure prevented increased expression and permitted regeneration in the presence of BDP. We demonstrated that BDP exposure increased expression in mouse embryonic stem cells and that regulation of by GCs is conserved in mammals.
我们之前利用斑马鱼幼体采用化学遗传学方法来鉴定组织再生的小分子抑制剂。这导致发现糖皮质激素（GC）通过糖皮质激素受体（GR）的不适当激活来阻断组织再生的早期阶段。我们进行了微阵列分析，以鉴定在再生鳍的形态发生过程中与倍氯米松二丙酸酯（BDP）暴露相关的基因表达变化。癌胚蛋白在BDP处理的再生组织中表达增加了八倍以上。我们假设癌胚蛋白的错误表达对于BDP阻断再生至关重要。在存在BDP的情况下，GR morphants中癌胚蛋白的表达未升高，这表明癌胚蛋白的诱导是GR依赖性的。在存在BDP的情况下，对Cripto-1进行部分翻译抑制可恢复组织再生。视黄酸暴露可防止癌胚蛋白表达增加，并在存在BDP的情况下允许再生。我们证明BDP暴露会增加小鼠胚胎干细胞中癌胚蛋白的表达，并且GC对癌胚蛋白的调节在哺乳动物中是保守的。
