Molecular links among the causative genes for ocular malformation:: Otx2 and Sox2 coregulate Rax expression
Molecular links among the causative genes for ocular malformation:: Otx2 and Sox2 coregulate Rax expression
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DOI：
10.1073/pnas.0710954105
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发表时间：
2008-04-08
影响因子：
11.1
通讯作者：
Asashima, Makoto
中科院分区：
文献类型：
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作者：
Danno, Hiroki;Michiue, Tatsuo;Asashima, Makoto
神经相关基因 Sox2、Pax6、OtK2 和 Rax 与严重的眼部畸形（如无眼症和小眼症）有关，但目前尚不清楚这些基因如何在功能上关联。我们分析了非洲爪蟾 Rax（也称为 Rx1）的上游信号传导，并确定 Otx2 和 Sox2 蛋白是 Rax 的直接上游调节因子。我们发现内源 Otx2 和 Sox2 蛋白与位于 Rax 启动子上游约 2 kb 的保守非编码序列 (CNS1) 结合。该序列在脊椎动物中是保守的，并且是有效转录活性所必需的。报告基因检测显示，Otx2 和 Sox2 通过 CNS1 协同激活转录。此外，Otx2 和 Sox2 蛋白之间存在物理相互作用，并且这种相互作用受到这些眼部疾病中发现的 Sox2 错义突变的影响。这些结果表明，Otx2 和 Sox2 蛋白之间的直接相互作用和相互依赖性协调眼睛发育中的 Rax 表达，提供了导致眼睛畸形的基因之间的分子联系。
The neural-related genes Sox2, Pax6, OtK2, and Rax have been associated with severe ocular malformations such as anophthalmia and microphthalmia, but it remains unclear as to how these genes are linked functionally. We analyzed the upstream signaling of Xenopus Rax (also known as Rx1) and identified the Otx2 and Sox2 proteins as direct upstream regulators of Rax. We revealed that enclogenous Otx2 and Sox2 proteins bound to the conserved noncoding sequence (CNS1) located approximate to 2 kb upstream of the Rax promoter. This sequence is conserved among vertebrates and is required for potent transcriptional activity. Reporter assays showed that Otx2 and Sox2 synergistically activated transcription via CNS1.. Furthermore, the Otx2 and Sox2 proteins physically interacted with each other, and this interaction was affected by the Sox2-missense mutations identified in these ocular disorders. These results demonstrate that the direct interaction and interdependence between the Otx2 and Sox2 proteins coordinate Rax expression in eye development, providing molecular linkages among the genes responsible for ocular malformation.