Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA.
J Biol Chem. 2011 Feb 25;286(8):6542-53. doi: 10.1074/jbc.M110.198382. Epub 2010 Dec 7.
All-trans-retinoic acid (atRA) stimulates neurogenesis, dendritic growth of hippocampal neurons, and higher cognitive functions, such as spatial learning and memory formation. Although astrocyte-derived atRA has been considered a key factor in neurogenesis, little direct evidence identifies hippocampus cell types and the enzymes that biosynthesize atRA. Here we show that primary rat astrocytes, but not neurons, biosynthesize atRA using multiple retinol dehydrogenases (Rdh) of the short chain dehydrogenase/reductase gene family and retinaldehyde dehydrogenases (Raldh). Astrocytes secrete atRA into their medium; neurons sequester atRA. The first step, conversion of retinol into retinal, is rate-limiting. Neurons and astrocytes both synthesize retinyl esters and reduce retinal into retinol. siRNA knockdown indicates that Rdh10, Rdh2 (mRdh1), and Raldh1, -2, and -3 contribute to atRA production. Knockdown of the Rdh Dhrs9 increased atRA synthesis ∼40% by increasing Raldh1 expression. Immunocytochemistry revealed cytosolic and nuclear expression of Raldh1 and cytosol and perinuclear expression of Raldh2. atRA autoregulated its concentrations by inducing retinyl ester synthesis via lecithin:retinol acyltransferase and stimulating its catabolism via inducing Cyp26B1. These data show that adult hippocampus astrocytes rely on multiple Rdh and Raldh to provide a paracrine source of atRA to neurons, and atRA regulates its own biosynthesis in astrocytes by directing flux of retinol. Observation of cross-talk between Dhrs9 and Raldh1 provides a novel mechanism of regulating atRA biosynthesis.
全反式视黄酸（atRA）可刺激神经发生、海马神经元的树突生长和更高的认知功能，如空间学习和记忆形成。尽管星形胶质细胞衍生的 atRA 被认为是神经发生的关键因素，但很少有直接证据确定海马细胞类型和生物合成 atRA 的酶。在这里，我们表明原代大鼠星形胶质细胞而非神经元使用短链脱氢酶/还原酶基因家族的多种视黄醇脱氢酶（Rdh）和视黄醛脱氢酶（Raldh）生物合成 atRA。星形胶质细胞将 atRA 分泌到其培养基中；神经元则隔离 atRA。第一步，将视黄醇转化为视黄醛，是限速步骤。神经元和星形胶质细胞都合成视黄醇酯并将视黄醛还原为视黄醇。siRNA 敲低表明 Rdh10、Rdh2（mRdh1）和 Raldh1、-2 和-3 有助于 atRA 的产生。Dhrs9 的 Rdh 敲低通过增加 Raldh1 的表达将 atRA 的合成增加了约 40%。免疫细胞化学显示 Raldh1 的细胞质和核表达以及 Raldh2 的细胞质和核周表达。atRA 通过诱导卵磷脂：视黄醇酰基转移酶合成视黄醇酯来自我调节其浓度，并通过诱导 Cyp26B1 来刺激其分解代谢。这些数据表明，成年海马星形胶质细胞依赖多种 Rdh 和 Raldh 为神经元提供旁分泌来源的 atRA，atRA 通过指导视黄醇的通量来调节其自身在星形胶质细胞中的生物合成。观察 Dhrs9 和 Raldh1 之间的串扰提供了调节 atRA 生物合成的新机制。
