摘要
All-trans-retinoic acid (atRA) is an important morphogen involved in many developmental processes, including neural differentiation, body axis formation, and organogenesis. During early embryonic development, atRA is synthesized from all-trans-retinal (atRAL) in an irreversible reaction mainly catalyzed by retinal dehydrogenase 2 (aldh1a2), whereas atRAL is converted from all-trans-retinol via reversible oxidation by retinol dehydrogenases, members of the short-chain dehydrogenase/reductase family. atRA is degraded by cytochrome P450, family 26 (cyp26). We have previously identified a short-chain dehydrogenase/reductase 3 (dhrs3), which showed differential expression patterns in Xenopus embryos. We show here that the expression of dhrs3 was induced by atRA treatment and overexpression of Xenopus nodal related 1 (xnr1) in animal cap assay. Overexpression of dhrs3 enhanced the phenotype of excessive cyp26a1. In embryos overexpressing aldh1a2 or retinol dehydrogenase 10 (rdh10) in the presence of their respective substrates, Dhrs3 counteracted the action of Aldh1a2 or Rdh10, indicating that retinoic acid signaling is attenuated. Knockdown of Dhrs3 by antisense morpholino oligonucleotides resulted in a phenotype of shortened anteroposterior axis, reduced head structure, and perturbed somitogenesis, which were also found in embryos treated with an excess of atRA. Examination of the expression of brachyury, not, goosecoid, and papc indicated that convergent extension movement was defective in Dhrs3 morphants. Taken together, these studies suggest that dhrs3 participates in atRA metabolism by reducing atRAL levels and is required for proper anteroposterior axis formation, neuroectoderm patterning, and somitogenesis.
摘要译文
全反式维甲酸（ATRA）是参与许多发育过程，包括神经分化，体轴形成和器官发生的重要形态发生。在早期胚胎发育，全反式维甲酸，从全反式视黄醛（atRAL）中的不可逆反应，主要催化视网膜脱氢酶2（aldh1a2）中合成，而atRAL选自全反式 - 视黄醇通过可逆氧化的视黄醇脱氢酶转化，短链脱氢酶/还原酶家族的成员。全反式维甲酸是通过细胞色素P450降解，家庭26（cyp26）。我们先前已经确定了短链脱氢酶/还原酶3（dhrs3），这表明在非洲爪蟾胚胎中的差异表达模式。我们在这里显示，dhrs3的表达诱导全反式维甲酸治疗和过表达爪蟾的节点相关1（xnr1）在动物帽测定。dhrs3的过表达增强过度CYP26A1的表型。在胚胎在各自基板的存在下过表达aldh1a2或视黄醇脱氢酶10（rdh10），Dhrs3抵消Aldh1a2或Rdh10的作用，这表明维甲酸信令衰减。Dhrs3的反义寡核苷酸吗啉击倒导致缩短前后轴，减少了头部结构的表型和扰动体节形成，其中也发现用过量的全反式维甲酸治疗胚胎。检查的Brachyury的表达，而不是，goosecoid，和PAPC表明收敛延长运动是有缺陷的Dhrs3 morphants。两者合计，这些研究表明，dhrs3参与全反式维甲酸代谢通过降低atRAL水平和所需的适当的前后轴形成，神经外胚层构图，和体节形成。
Richard Kin Ting Kam[‡][1][2]; Weili Shi[§][1][2]; Sun On Chan[¶]; Yonglong Chen[‖]; Gang Xu[§]; Clara Bik-San Lau**; Kwok Pui Fung[‡]; Wood Yee Chan[¶][3] and Hui Zhao[‡];[‡‡][4]. Dhrs3 Protein Attenuates Retinoic Acid Signaling and Is Required for Early Embryonic Patterning*[J]. Journal of Biological Chemistry, 2013,288(44): 31477-31487