Genetic dissection of retinoid dehydrogenases
Genetic dissection of retinoid dehydrogenases
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DOI：
10.1016/s0009-2797(00)00292-1
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发表时间：
2001-01-30
影响因子：
5.1
通讯作者：
Duester, G
中科院分区：
文献类型：
--
作者：
Duester, G
生化研究表明，乙醇脱氢酶 (ADH) 将视黄醇代谢为视黄醛，乙醛脱氢酶 (ALDH) 将视黄醛代谢为视黄酸，视黄酸是生长和发育所必需的分子。本文总结了几项支持 ADH 和 ALDH 在视黄酸合成中的体内功能的遗传学研究。基因打靶用于创建 Adh1 或 Adh4 基因敲除小鼠。两只基因敲除小鼠均能存活且具有生育能力，没有明显缺陷。然而，当野生型和Adh4敲除小鼠在妊娠期间缺乏维生素A时，Adh4敲除小鼠出生时的存活率会降低3.3倍。当检查成年小鼠在施用视黄醇后视黄酸的产生情况时，与野生型相比，Adh1 敲除小鼠的肝脏中视黄酸水平降低了 10 倍，而 Adh4 敲除小鼠与野生型的差异不到 2 倍。因此，Adh1 在成人大剂量视黄醇代谢为视黄酸中起主要作用，而 Adh4 在视黄醇缺乏期间维持足够的视黄醇代谢以促进发育中发挥作用。通过青蛙胚胎中的过度表达研究来检查 ALDH。注射小鼠 Raldh1 或 Raldh2 的 mRNA 会刺激处于囊胚阶段的青蛙胚胎中视黄酸的合成，而此时视黄酸通常是检测不到的。人 ALDH2、人 ALDH3 和小鼠 Aldh-pb 的过度表达不会刺激视黄酸的产生。此外，Raldh2 基因敲除小鼠表现出胚胎致死性，且视黄醇依赖性组织存在缺陷。总体而言，这些研究提供了遗传证据，证明 Adh1、Adh4、Raldh1 和 Raldh2 编码参与体内视黄酸合成的类视黄醇脱氢酶。 (C) 2001 Elsevier Science Ireland Ltd. 保留所有权利。
Biochemical studies indicate that alcohol dehydrogenase (ADH) metabolizes retinol to retinal, and that aldehyde dehydrogenase (ALDH) metabolizes retinal to retinoic acid, a molecule essential for growth and development. Summarized herein are several genetic studies supporting in vivo functions for ADH and ALDH in retinoic acid synthesis. Gene targeting was used to create knockout mice for either Adh1 or Adh4. Both knockout mice were viable and fertile without obvious defects. However, when wild-type and Adh4 knockout mice were subjected to vitamin A deficiency during gestation, the survival rate at birth was 3.3-fold lower for Adh4 knockout mice. When adult mice were examined for production of retinoic acid following retinol administration, Adh1 knockout mice exhibited 10-fold lower retinoic acid levels in liver compared with wild-type, whereas Adh4 knockout mice differed from wild-type by less than 2-fold. Thus, Adh1 plays a major role in the metabolism of a large dose of retinol to retinoic acid in adults, whereas Adh4 plays a role in maintaining sufficient retinol metabolism for development during retinol deficiency. ALDHs were examined by overexpression studies in frog embryos. Injection of mRNAs for either mouse Raldh1 or Raldh2 stimulated retinoic acid synthesis in frog embryos at the blastula stage when retinoic acid is normally undetectable. Overexpression of human ALDH2, human ALDH3, and mouse Aldh-pb did not stimulate retinoic acid production. In addition, Raldh2 knockout mice exhibit embryonic lethality with defects in retinoid-dependent tissues. Overall, these studies provide genetic evidence that Adh1, Adh4, Raldh1, and Raldh2 encode retinoid dehydrogenases involved in retinoic acid synthesis in vivo. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.