Convergence of a head-field selector Otx2 and Notch signaling: a mechanism for lens specification
Convergence of a head-field selector Otx2 and Notch signaling: a mechanism for lens specification
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DOI：
10.1242/dev.009548
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发表时间：
2008-01-15
期刊：
影响因子：
4.6
通讯作者：
Grainger, Robert M.
中科院分区：
文献类型：
--
作者：
Ogino, Hajime;Fisher, Marilyn;Grainger, Robert M.
非洲爪蟾是系统解码顺式调控网络的理想选择，因为它在脊椎动物中的进化位置允许人们将联合收割机比较基因组学与高效的转基因技术结合在一个系统中。在这里，我们已经确定并分析了主要增强子FoxE3（Lens1），一个基因的透镜形成是必不可少的激活时，在假定的透镜外胚层（PLE）的承诺发生的透镜的命运。基于爪蟾和哺乳动物序列的比较以及体外和体内结合测定的增强子的缺失和突变分析鉴定了两种必需的转录调节因子：Otx 2，一种在包括PLE的头部外胚层中广泛表达的同源结构域蛋白，和Su（H），一种Notch信号传导的核信号转导子。Notch配体Delta2在PLE附近的视泡中表达，抑制其活性导致FoxE3表达丧失或严重减少，随后基板形成失败。Notch信号转导的异位激活诱导了表达Otx 2的头部外胚层内的FoxE3表达，并且在躯干外胚层中的Otx 2的额外错误表达向后延长了Notch诱导的FoxE3表达。这些数据提供了Notch信号转导参与透镜诱导的第一个直接证据。在靶顺式调节元件内，场选择器（Otx 2）和定位信号（Notch）的输入的专性整合可能是脊椎动物中器官场特化的一般机制（如在果蝇中）。这一概念也与涉及“多步诱导”的许多器官系统的经典胚胎学研究一致。
Xenopus is ideal for systematic decoding of cis-regulatory networks because its evolutionary position among vertebrates allows one to combine comparative genomics with efficient transgenic technology in one system. Here, we have identified and analyzed the major enhancer of FoxE3 (Lens1), a gene essential for lens formation that is activated in the presumptive lens ectoderm (PLE) when commitment to the lens fate occurs. Deletion and mutation analyses of the enhancer based on comparison of Xenopus and mammalian sequences and in vitro and in vivo binding assays identified two essential transcriptional regulators: Otx2, a homeodomain protein expressed broadly in head ectoderm including the PLE, and Su(H), a nuclear signal transducer of Notch signaling. A Notch ligand, Delta2, is expressed in the optic vesicle adjacent to the PLE, and inhibition of its activity led to loss, or severe reduction, of FoxE3 expression followed by failure of placode formation. Ectopic activation of Notch signaling induced FoxE3 expression within head ectoderm expressing Otx2, and additional misexpression of Otx2 in trunk ectoderm extended the Notch-induced FoxE3 expression posteriorly. These data provide the first direct evidence of the involvement of Notch signaling in lens induction. The obligate integration of inputs of a field-selector (Otx2) and localized signaling (Notch) within target cis-regulatory elements might be a general mechanism of organ-field specification in vertebrates (as it is in Drosophila). This concept is also consistent with classical embryological studies of many organ systems involving a 'multiple-step induction'.