title: All-trans-retinoic acid induces short forelimb malformation during mouse embryo development by inhibiting chondrocyte maturation rather than by evoking excess cell death.
abstract: 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.
authors.affiliation: School of Medicine, Hunan Normal University, Changsha 410013, PR China.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Hongping
authors.initials: H
authors.lastname: Yin
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Zhou
authors.forename: Xuying
authors.initials: X
authors.lastname: Wan
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Zhu
authors.forename: Tianbao
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology; D019902:Chondrocytes / Q000187:drug effects*; D056750:Cyclin A1 / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D005260:Female; D005552:Forelimb / Q000002:abnormalities*; D006651:Histocytochemistry; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000633:toxicity*; D056811:Unfolded Protein Response
chemical_list: C503747:Ccna1 protein, mouse; C534700:Ccnb1 protein, mouse; D056750:Cyclin A1; D056744:Cyclin B1; D012333:RNA, Messenger; D014212:Tretinoin