Interplay of Pax6 and SOX2 in lens development as a paradigm of genetic switch mechanisms for cell differentiation
Interplay of Pax6 and SOX2 in lens development as a paradigm of genetic switch mechanisms for cell differentiation
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DOI：
10.1387/ijdb.041868hk
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发表时间：
2004-01-01
影响因子：
0.7
通讯作者：
Kamachi, Y
中科院分区：
文献类型：
--
作者：
Kondoh, H;Uchikawa, M;Kamachi, Y
当克隆时代到来时，我们的第一个克隆目标是鸡的delta 1-晶状体蛋白基因，该晶状体特异性基因在透镜诱导后最早表达。我们研究了该基因的调控，认为其激活机制必须反映透镜分化本身。我们在这里总结了我们小组沿着这条路线在过去20年中进行的调查。delta 1-晶状体蛋白基因由第三内含子中的增强子调节，并且这种调节的特异性由由两个转录因子结合的仅30 bp DNA的DNA区域（称为DC 5）控制。这些因子已被鉴定为SOX 1/2/3（B1组SOX蛋白，SOX 2是主要参与者）和Pax 6，并且已显示协同结合DC 5并形成具有强大的转录激活效力的三元复合物。在胚胎中，Pax 6在透镜形成之前在头部外胚层中广泛表达，并且随着视泡与外胚层接触，在外胚层的接触区域中诱导SOX 2/3表达，从而允许Pax 6和SOX 2/3在相同的细胞核中相遇，在那里它们然后可以激活用于早期透镜发育的一系列基因，包括δ 1晶状体蛋白。因此，Pax 6和SOX 2的协同作用启动了透镜分化。更广泛地说，SOX 1/2/3与各种伴侣转录因子相互作用，并参与定义依赖于伴侣因子的不同细胞状态：Pax 6用于透镜分化，Oct 3/4用于建立外胚层/ES细胞状态，Brn 2用于神经原基。因此，SOX 2（和SOX 1/3）及其伴侣因子（以Pax 6为例）的调节决定了细胞分化发生的时空顺序。
When the cloning era arrived, our first target for cloning was the delta1-crystallin gene of the chicken, the lens-specific gene expressed earliest following lens induction. We have investigated the regulation of this gene with the idea that the mechanism of its activation must reflect that of lens differentiation per se. We here summarize the investigation carried out in our group along this line over the past 20 years. The delta1-crystallin gene is regulated by an enhancer in the third intron, and the specificity of this regulation is governed by a DNA region (called DC5) of only 30 bp DNA bound by two transcription factors. These factors have been identified as SOX1/2/3 (Group B1 SOX proteins, SOX2 being the major player) and Pax6, and have been shown to bind cooperatively to DC5 and form a ternary complex having a robust potency for transcriptional activation. In the embryo, Pax6 is widely expressed in the head ectoderm before the lens is formed, and as the optic vesicle comes into contact with the ectoderm, SOX2/3 expression is induced in the contacted area of the ectoderm, thereby allowing Pax6 and SOX2/3 to meet in the same cell nucleus, where they can then activate a battery of genes for early lens development including delta1crystallin. Thus, the cooperative action of Pax6 and SOX2 initiates lens differentiation. More broadly, SOX1 /2/3 interact with various partner transcription factors, and participate in defining distinct cell states that depend on the partner factors: Pax6 for lens differentiation, Oct3/4 for establishing the epiblast/ES cell state, and Brn2 for the neural primordia. Thus, the regulation of SOX2 (and SOX1/3) and its partner factors, exemplified by Pax6, determines the spatio-temporal order of the occurrence of cell differentiation.