Loss of the maternal imprint in Dnmt3Lmat-/- mice leads to a differentiation defect in the extraembryonic tissue
Loss of the maternal imprint in Dnmt3Lmat-/- mice leads to a differentiation defect in the extraembryonic tissue
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DOI：
10.1016/j.ydbio.2006.05.003
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发表时间：
2006-09-15
影响因子：
2.7
通讯作者：
Wake, Norio
中科院分区：
文献类型：
--
作者：
Arima, Takahiro;Hata, Kenichiro;Wake, Norio
基因组DNA甲基化对哺乳动物的发育至关重要，并在包括基因组印记在内的各种生物学过程中起着至关重要的作用。虽然DNA甲基转移酶3样（Dnmt 3L）蛋白缺乏DNA甲基化酶活性，但它被认为与功能性DNA甲基转移酶结合建立母体印记。在Dnmt 3L靶向缺失纯合子的雌性小鼠中，卵子发生显然正常进行，但它们的杂合子后代（Dnmt 3Lmat（-/-））由于印迹缺陷而在妊娠中期前死亡。在这项研究中，我们表明，Dnmt 3L是必需的建立母体甲基化印记在胚胎和胎盘，这些胚胎的胎盘发育异常。迷路的形成有缺陷，海绵滋养层的形成减少，滋养层巨细胞过多，绒毛膜层和外胎盘锥之间的附着不足。此外，我们证明逮捕增殖的胚外组织在体内没有细胞凋亡和干扰的细胞命运的Dnmt 3L（垫-/-）滋养层干细胞在体外。此外，我们报告，DNA甲基化在卵子发生过程中是必不可少的印记Mash 2的建立。这些发现提供了证据，不仅是DNA甲基化所需的适当的母体印记在胎盘，但适当的印记是绝对需要的脊椎动物胎盘。(c)2006年爱思唯尔公司All rights reserved.
DNA methylation of the genome is essential for mammalian development and plays crucial roles in a variety of biological processes including genomic imprinting. Although the DNA methyltransferase 3-like (Dnmt3L) protein lacks DNA methylase activity, it is thought to establish the maternal imprint in combination with the functional DNA methyltransferases. Oogenesis apparently proceeds normally in female mice homozygous for a targeted deletion of Dnmt3L, but their heterozygous offspring (Dnmt3Lmat(-/-)) die before midgestation due to an imprinting defect. In this study, we show that Dnmt3L is required for the establishment of maternal methylation imprints both in the embryos and the placentae and that the placentae of these embryos develop abnormally. There is a defect in the formation of the labyrinth, reduced formation of the spongiotrophoblast layer, excess trophoblast giant cells and insufficient attachment between the chorion layer and the ectoplacental cone. In addition, we demonstrate arrest of proliferation of the extraembryonic tissue without apoptosis in vivo and a disturbance of the cell fate of Dnmt3L(mat-/-) trophoblastic stem cells in vitro. Furthermore, we report that DNA methylation during oogenesis is essential for the establishment of imprinting Mash2. These findings provide evidence that not only is DNA methylation required for the appropriate maternal imprint in the placenta but that the appropriate imprint is absolutely required for vertebrate placentation. (c) 2006 Elsevier Inc. All rights reserved.