All-trans-retinoic acid induces short forelimb malformation during mouse embryo development by inhibiting chondrocyte maturation rather than by evoking excess cell death

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• 作者：Yongfei Zhu^a ; ^b ; ¹ ; Yuping Zhu^b ; ¹ ; Hongping Yin^c ; Hongyuan Zhou^b ; Xuying Wan^b ; Jiangbo Zhu^b ; Tianbao Zhang^b ; ^{tbzhang2009@yeah.net}
• 关键词：All-trans-retinoic acid ; Short forelimbs ; Unfolded protein response ; Cyclins
• 刊名：Toxicology Letters
• 出版年：2012
• 期刊代码：49_03784274
• 类别：pha
• 出版时间：1 June, 2012
• 卷：211
• 期：2
• 页码：172-186
• 文件大小：4728 K

摘要

Various biochemical and physiological stimuli may interfere with endoplasmic reticulum (ER) homeostasis, causing aggregation and accumulation of unfolded or malfolded proteins in the ER and resulting in ER stress (ERS), and the ER attenuates ERS through unfolded protein response (UPR). All-trans-retinoic acid (ATRA) can enhance or attenuate some ERS-induced physiological or pathological changes. Our previous studies showed that there was UPR in short forelimbs induced by ATRA. Many kinds of malformations induced by ATRA may correlate with cell death, and knowing that UPR is closely associated with cell death, so we speculate that the short forelimbs may caused by UPR-induced cell death. To test this hypothesis, the present study investigated the expression of UPR-related genes and proteins in the same short forelimb malformation model to determine whether ATRA-induced short forelimb malformation occurred through UPR-induced cell death. Subsequently, we further observed the differentiation and proliferation of chondrocytes and the expression of related genes and/or proteins. It was found that ATRA evoked UPR in this short forelimb model, thus activating the anti-cell death pathway and inhibiting the cell death-promoting pathway. Cell death was not evident in short forelimb, and ATRA inhibited the expression of Ccnb1 and Ccna1, thus retarding chondrocyte maturation. As a result, the number of immature chondrocytes in short forelimb was greater than the normal level. We therefore believe that ATRA induces short forelimb malformation most likely by inhibiting chondrocyte maturation rather than by evoking excess cell death.