PAX6 and SOX2-dependent regulation of the Sox2 enhancer N-3 involved in embryonic visual system development
PAX6 and SOX2-dependent regulation of the Sox2 enhancer N-3 involved in embryonic visual system development
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DOI：
10.1111/j.1365-2443.2007.01114.x
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发表时间：
2007-09-01
期刊：
影响因子：
2.1
通讯作者：
Kondoh, Hisato
中科院分区：
文献类型：
--
作者：
Inoue, Masashi;Kamachi, Yusuke;Kondoh, Hisato
Sox2在早期胚胎的神经原基和胎盘原基中普遍表达，这种表达依赖于各种具有不同区域和时间特异性的系统发育保守增强子。增强子N-3被鉴定为Sox2基因在间脑、视神经囊泡以及视神经囊泡与外胚层接触后晶状体placodal表面活跃的调节因子，提示其参与胚胎视觉系统的发育。在568 bp长的增强子N-3中定义了一个36 bp的最小核心序列，该序列以四聚体的形式模拟了原始增强子的活性。核心序列包括一个SOX2结合序列和一个非典型PAX6 （Paired domain）结合序列，在转染细胞中被SOX2和PAX6的协同作用激活。N-3核心的SOX和PAX6结合序列与先前被证明与SOX2和PAX6协同结合的三角结晶蛋白增强子的DC5序列排列方向和间距相同。N-3核心序列也被这些因子协同结合，但这些因子水平的阈值高于DC5，外源SOX2和PAX6激活的四聚体序列的增强作用不如DC5明显。这些观察结果表明，依赖于SOX2和PAX6的协同相互作用但具有不同因子水平阈值的基因激活机制对视觉系统发育的调控至关重要。
Sox2 is universally expressed in the neural and placodal primordia in early stage embryos, and this expression depends on various phylogenetically conserved enhancers having different regional and temporal specificities. The enhancer N-3 was identified as a regulator of the Sox2 gene active in the diencephalon, optic vesicle, and after the contact of the vesicle with the ectoderm, in the lens placodal surface area, suggesting its involvement in embryonic visual system development. A 36-bp minimal essential core sequence was defined in the 568-bp-long enhancer N-3, which in a tetrameric form emulates the original enhancer activity. The core sequence comprises a SOX-binding sequence and a non-canonical PAX6 (Paired domain) binding sequence, and is activated by the synergistic action of SOX2 and PAX6 in transfected cells. The SOX and PAX6 binding sequences of the N-3 core are arranged with the same orientation and spacing as the DC5 sequence of the delta-crystallin enhancer previously demonstrated to be cooperatively bound by SOX2 and PAX6. The N-3 core sequence was also bound by these factors in a cooperative fashion, but with a higher threshold of these factors' levels than DC5, and the enhancer effect of the tetrameric sequence activated by exogenous SOX2 and PAX6 was less pronounced than that of DC5. The observations suggest that gene activation mechanisms that depend on the cooperative interaction of SOX2 and PAX6 but with different thresholds of the factor levels are crucial for the regulation of visual system development.