Regulation of Otx2 expression and its functions in mouse forebrain and midbrain
Regulation of Otx2 expression and its functions in mouse forebrain and midbrain
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DOI：
10.1242/dev.01220
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发表时间：
2004-07-01
期刊：
影响因子：
4.6
通讯作者：
Aizawa, S
中科院分区：
文献类型：
--
作者：
Kurokawa, D;Kiyonari, H;Aizawa, S
发现前脑和中脑中的 Otx2 表达受到位于 75 kb 5' 上游和 115 kb 3' 下游的两个不同增强子（FM 和 FM2）的调节。 E8.0之前的前神经外胚层中不存在这两种增强子的活性；然而，在E9.5，它们的活动区域跨越整个中脑和间脑，其尾部限制在与中脑或峡部的边界处。在端脑中，仅在背内侧发现活动。 OTX 和 TCF 的潜在结合位点对于 FM 活性至关重要，TCF 位点对于 FM2 活性也至关重要。 FM2 增强子似乎是啮齿类动物所独有的；然而，FM 增强子区域在有颚动物中是高度保守的。对缺乏 FM 或 FM2 增强子的突变体的研究表明，这些增强子确实调节前脑和中脑中的 Otx2 表达。中脑和间脑区域的发育通过 FM 和 FM2 增强剂下 Otx1 和 Otx2 之间的合作以剂量依赖性方式进行差异调节：结构越靠近尾部，OTX 剂量需求越高。在E10.5 Otx1(-/-)Otx2(DeltaFM/DeltaFM)突变体中，FM2增强子下的Otx2表达仍然存在，表现出整个间脑和中脑几乎完全丧失；然而，端脑确实发育了。
Otx2 expression in the forebrain and midbrain was found to be regulated by two distinct enhancers (FM and FM2) located at 75 kb 5' upstream and 115 kb 3' downstream. The activities of these two enhancers were absent in anterior neuroectoderm earlier than E8.0; however, at E9.5 their regions of activity spanned the entire mesencephalon and diencephalon with their caudal limits at the boundary with the metencephalon or isthmus. In telencephalon, activities were found only in the dorsomedial aspect. Potential binding sites of OTX and TCF were essential to FM activity, and TCF sites were also essential to FM2 activity. The FM2 enhancer appears to be unique to rodent; however, the FM enhancer region is deeply conserved in gnathostomes. Studies of mutants lacking FM or FM2 enhancer demonstrated that these enhancers indeed regulate Otx2 expression in forebrain and midbrain. Development of mesencephalic and diencephalic regions was differentially regulated in a dose-dependent manner by the cooperation between Otx1 and Otx2 under FM and FM2 enhancers: the more caudal the structure the higher the OTX dose requirement. At E10.5 Otx1(-/-)Otx2(DeltaFM/DeltaFM) mutants, in which Otx2 expression under the FM2 enhancer remained, exhibited almost complete loss of the entire diencephalon and mesencephalon; the telencephalon did, however, develop.