Spatial and temporal regulation of Wnt/β-catenin signaling is essential for development of the retinal pigment epithelium
Spatial and temporal regulation of Wnt/β-catenin signaling is essential for development of the retinal pigment epithelium
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DOI：
10.1016/j.ydbio.2009.07.002
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发表时间：
2009-10-01
影响因子：
2.7
通讯作者：
Kozmik, Zbynek
中科院分区：
文献类型：
--
作者：
Fujimura, Naoko;Taketo, Makoto M.;Kozmik, Zbynek
在眼睛发育过程中，Wnt/ β -连环蛋白信号在视网膜背侧色素上皮（RPE）中高度活跃。为了研究Wnt/ β - catenin信号在RPE发展中的作用，我们在小鼠中使用条件Cre/loxP系统灭活或异位激活RPE中的Wnt/ β - catenin信号。Wnt/ β -catenin信号的失活导致RPE向神经视网膜（NR）的转分化，RPE特异性标记物Mitf和Otx2的下调以及NR特异性标记物Chx10和Rx的异位表达分别证明了这一点。相反，Wnt/ β -catenin信号的异位激活会导致RPE模式的破坏，这表明Wnt/ β -catenin信号的精确时空调节是正常RPE发育所必需的。通过染色质免疫沉淀（ChIP）和报告基因检测，我们提供了证据，证明Otx2和rpe特异性Mitf亚型Mitf- h是Wnt/ β -连环蛋白信号传导的直接转录靶点。综上所述，我们的数据表明Wnt/ β -catenin信号通过维持或诱导Mitf和Otx2的表达，在RPE的发展中起着至关重要的作用。(C) 2009爱思唯尔公司版权所有。
Wnt/beta catenin signaling is highly active in the dorsal retinal pigment epithelium (RPE) during eye development. To study the role of Wnt/beta- catenin signaling in the RPE development we used a conditional Cre/loxP system in mice to inactivate or ectopically activate Wnt/beta- catenin signaling in the RPE. Inactivation of Wnt/beta-catenin signaling results in transdifferentiation of RPE to neural retina (NR) as documented by downregulation of RPE-specific markers Mitf and Otx2 and ectopic expression of NR-specific markers Chx10 and Rx, respectively. In contrast, ectopic activation of Wnt/beta-catenin signaling results in the disruption of the RPE patterning, indicating that precise spatial and temporal regulation of Wnt/beta-catenin signaling is required for normal RPE development. Using chromatin immunoprecipitation (ChIP) and reporter gene assays we provide evidence that Otx2 and RPE-specific isoform of Mitf, Mitf-H, are direct transcriptional targets of Wnt/beta-catenin signaling. Combined, our data suggest that Wnt/beta-catenin signaling plays an essential role in development of RPE by maintaining or inducing expression of Mitf and Otx2. (C) 2009 Elsevier Inc. All rights reserved.