Perez-Castro A V, Tran V T, Nguyen-Huu M C
Department of Microbiology, Columbia University, New York, New York 10032.
Development. 1993 Oct;119(2):363-75. doi: 10.1242/dev.119.2.363.
All-trans retinoic acid, a metabolite of retinol, is a possible morphogen in vertebrate development. Two classes of cellular proteins, which specifically bind all-trans retinoic acid, are thought to mediate its action: the nuclear retinoic acid receptors (RAR alpha, beta, gamma), and the cytoplasmic binding proteins known as cellular retinoic acid-binding proteins I and II (CRABP I and II). The function of the retinoic acid receptors is to regulate gene transcription by binding to DNA in conjunction with the nuclear retinoid X receptors (RXR alpha, beta, gamma), which in turn have 9-cis retinoic acid as a ligand. Several lines of evidence suggest that the role of the cellular retinoic acid-binding proteins is to control the concentration of free retinoic acid reaching the nucleus in a given cell. Here, we have addressed the role of the cellular retinoic acid-binding protein I in development by ectopically expressing it in the mouse lens, under the control of the alpha A-crystallin promoter. We show that this ectopic expression interferes with the development of the lens and with the differentiation of the secondary lens fiber cells, causing cataract formation. These results suggest that correct regulation of intracellular retinoic acid concentration is required for normal eye development. In addition, the generated transgenic mice also present expression of the transgene in the pancreas and develop pancreatic carcinomas, suggesting that overexpression of the cellular retinoic acid-binding protein is the cause of the tumors. These results taken together provide evidence for a role of the cellular retinoic acid-binding protein in development and cell differentiation. The relevance of these findings to the possible role of the cellular retinoic acid-binding proteins in the transduction of the retinoic acid signal is discussed.
全反式视黄酸是视黄醇的一种代谢产物，可能是脊椎动物发育过程中的一种形态发生原。两类能特异性结合全反式视黄酸的细胞蛋白被认为可介导其作用：核视黄酸受体（RARα、β、γ），以及被称为细胞视黄酸结合蛋白I和II（CRABP I和II）的细胞质结合蛋白。视黄酸受体的功能是通过与核类视黄醇X受体（RXRα、β、γ）结合来调节基因转录，而核类视黄醇X受体又以9-顺式视黄酸作为配体。几条证据线索表明，细胞视黄酸结合蛋白的作用是控制到达特定细胞细胞核的游离视黄酸浓度。在此，我们通过在αA-晶体蛋白启动子的控制下在小鼠晶状体中异位表达细胞视黄酸结合蛋白I，来研究其在发育过程中的作用。我们发现这种异位表达会干扰晶状体的发育以及次级晶状体纤维细胞的分化，导致白内障形成。这些结果表明，正常的眼睛发育需要正确调节细胞内视黄酸浓度。此外，所产生的转基因小鼠在胰腺中也出现了转基因的表达，并发展出胰腺癌，这表明细胞视黄酸结合蛋白的过表达是肿瘤形成的原因。综合这些结果为细胞视黄酸结合蛋白在发育和细胞分化中的作用提供了证据。我们还讨论了这些发现与细胞视黄酸结合蛋白在视黄酸信号转导中可能作用的相关性。
