Regulation of Otx2 expression and its functions in mouse epiblast and anterior neuroectoderm
Regulation of Otx2 expression and its functions in mouse epiblast and anterior neuroectoderm
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DOI：
10.1242/dev.01219
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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：
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作者：
Kurokawa, D;Takasaki, N;Aizawa, S
我们在5‘上游约90kb的上胚层(EP)和前神经外胚层(AN)中发现了作用于OTX2表达的顺式调控序列。EP增强子的活性在E3.5的内细胞团中发现，在E5.5的整个上胚中发现。AN增强子的活性最初在E7.0检测到，到E8.5停止，后来在E10.5在端脑的背内侧发现。EP增强子包括超过2.3kb的多个必需结构域，AN增强子是EP增强子的重要组成部分。缺乏AN增强子的突变体已经证明，这些顺式序列确实调节了EP和AN中OTX2的表达。同时，我们的分析表明，另一个EP和增强子必须存在于-170kb到+120kb范围之外。在OTX2(DeltaAN/-)突变体中，如果一个OTX2等位基因缺乏增强子，另一个等位基因为空，则正常形成前后轴，并正常诱导前神经外胚层。然而，随后，前脑和中脑丢失，表明OTX2在AN增强子下的表达一旦被诱导，就具有维持前神经外胚层的功能。此外，AN增强子下的OTX2与Emx2在间脑发育中起协同作用。AN增强子区域在小鼠、人和非洲爪猴中都是保守的；此外，非洲爪哇的对应区在小鼠前神经外胚层中表现出增强活性。
We have identified cis-regulatory sequences acting on Otx2 expression in epiblast (EP) and anterior neuroectoderm (AN) at about 90 kb 5' upstream. The activity of the EP enhancer is found in the inner cell mass at E3.5 and the entire epiblast at E5.5. The AN enhancer activity is detected initially at E7.0 and ceases by E8.5; it is found later in the dorsomedial aspect of the telencephalon at E10.5. The EP enhancer includes multiple required domains over 2.3 kb, and the AN enhancer is an essential component of the EP enhancer. Mutants lacking the AN enhancer have demonstrated that these cis-sequences indeed regulate Otx2 expression in EP and AN. At the same time, our analysis indicates that another EP and AN enhancer must exist outside of the -170 kb to +120 kb range. In Otx2(DeltaAN/-) mutants, in which one Otx2 allele lacks the AN enhancer and the other allele is null, anteroposterior axis forms normally and anterior neuroectoderm is normally induced. Subsequently, however, forebrain and midbrain are lost, indicating that Otx2 expression under the AN enhancer functions to maintain anterior neuroectoderm once induced. Furthermore, Otx2 under the AN enhancer cooperates with Emx2 in diencephalon development. The AN enhancer region is conserved among mouse, human and Xenopus; moreover, the counterpart region in Xenopus exhibited an enhancer activity in mouse anterior neuroectoderm.