摘要
Retinoic acid (RA) is an important developmental signaling molecule responsible for the patterning of multiple vertebrate tissues. RA is also a potent teratogen, causing multi-organ birth defects in humans. Endogenous RA levels must therefore be tightly controlled in the developing embryo. We used a microarray approach to identify genes that function as negative feedback regulators of retinoic acid signaling. We screened for genes expressed in early somite-stage embryos that respond oppositely to treatment with RA versus RA antagonists and validated them by RNA in situ hybridization. Focusing on genes known to be involved in RA metabolism, we determined that dhrs3a, which encodes a member of the short-chain dehydrogenase/reductase protein family, is both RA dependent and strongly RA inducible. Dhrs3a is known to catalyze the reduction of the RA precursor all-trans retinaldehyde to vitamin A; however, a developmental function has not been demonstrated. Using morpholino knockdown and mRNA over-expression, we demonstrate that Dhrs3a is required to limit RA levels in the embryo, primarily within the central nervous system. Dhrs3a is thus an RA-induced feedback inhibitor of RA biosynthesis. We conclude that retinaldehyde availability is an important level at which RA biosynthesis is regulated in vertebrate embryos.
摘要译文
视黄酸（RA）是负责多个脊椎动物组织中的图案化的一个重要发育信号分子。类风湿性关节炎也是一种有效的致畸剂，引起多器官出生缺陷的人类。内源性的RA水平，因此必须严格控制在发育中的胚胎。我们使用微阵列的方式来确定基因的功能维甲酸信令的负反馈调节。我们筛选表达在早期体节阶段胚胎响应相对地治疗类风湿性关节炎与RA拮抗剂基因和原位杂交证实他们通过RNA。着眼于基因已知参与RA的代谢，我们确定dhrs3a，其编码的短链脱氢酶/还原酶蛋白家族的一个成员，既依赖于RA和RA强烈诱导。 Dhrs3a已知催化的RA前体全反式视黄醛为维生素A的还原;然而，一个发育功能尚未得到证实。用吗啉拦截和mRNA过度表达，我们表明，Dhrs3a需要限制的RA水平在胚胎，主要在中枢神经系统中。 Dhrs3a因此RA合成的RA引起的反馈抑制剂。我们的结论是视黄醛的可用性是其中RA生物合成调控在脊椎动物胚胎的一个重要层面。
L. Feng[a][b]; R.E. Hernandez[a][b][c]; J.S. Waxman[d]; D. Yelon[d]; C.B. Moens[a][b]. Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism[J]. Developmental Biology, 2010,338(1): 1–14