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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development
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Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

机译：腺瘤性息肉病菌在眼发育过程中调节视黄酸生物合成和Wnt的双重作用

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摘要

Congenital hypertrophy/hyperplasia of the retinal pigmented epithelium is an ocular lesion found in patients harboring mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. We report that Apc-deficient zebrafish display developmental abnormalities of both the lens and retina. Injection of dominant-negative Lef reduced Wnt signaling in the lens but did not rescue retinal differentiation defects. In contrast, treatment of apc mutants with all-trans retinoic acid rescued retinal differentiation defects but had no apparent effect on the lens. We identified Rdh5 as a retina-specific retinol dehydrogenase controlled by APC. Mor-pholino knockdown of Rdh5 phenocopied the apc mutant retinal differentiation defects and was rescued by treatment with exogenous all-trans retinoic acid. Microarray analyses of apc mutants and Rdh5 morphants revealed a profound overlap in the transcrip-tional profile of these embryos. These findings support a model wherein Apc serves a dual role in regulating Wnt and retinoic acid signaling within the eye and suggest retinoic acid deficiency as an explanation for APC mutation-associated retinal defects such as congenital hypertrophy/hyperplasia of the retinal pigmented epithelium.
机译：视网膜色素上皮的先天性肥大/增生是一种眼部病变，存在于腺瘤性息肉病大肠杆菌（APC）肿瘤抑制基因突变的患者中。我们报告说，缺乏Apc的斑马鱼显示出晶状体和视网膜的发育异常。显性阴性Lef注射可减少晶状体中的Wnt信号传导，但不能挽救视网膜分化缺陷。相反，用全反式视黄酸处理apc突变体可挽救视网膜分化缺陷，但对晶状体没有明显作用。我们确定Rdh5为APC控制的视网膜特异性视黄醇脱氢酶。 Rdh5的Mor-pholino击倒表型复制了apc突变体视网膜分化缺陷，并通过外源全反式维甲酸处理得以挽救。对apc突变体和Rdh5突变体进行的微阵列分析显示，这些胚胎的转录谱中存在严重的重叠。这些发现支持了这样一种模型，其中Apc在调节眼内的Wnt和视黄酸信号中起双重作用，并建议视黄酸缺乏作为与APC突变相关的视网膜缺陷（如先天性肥大/视网膜色素上皮增生）的解释。

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