Loss of the maternal imprint in Dnmt3Lmat-/- mice leads to a differentiation defect in the extraembryonic tissue

被引:71
作者
Arima, Takahiro [1 ]
Hata, Kenichiro
Tanaka, Satoshi
Kusumi, Maki
Li, En
Kato, Kiyoko
Shiota, Kunio
Sasaki, Hiroyuki
Wake, Norio
机构
[1] Kyushu Univ, Dept Mol Genet, Div Mol & Cell Therapeut, Med Inst Bioregulat, Oita 8740838, Japan
[2] Res Org Informat & Syst, Div Human Genet, Dept Integrated Genet, Natl Inst Genet, Mishima, Shizuoka 4118540, Japan
[3] Grad Univ Adv Studies, Dept Genet, Sch Life Sci, SOKENDAI, Mishima, Shizuoka 4118540, Japan
[4] Univ Tokyo, Lab Cellular Biochem, Dept Anim Resource Sci Vet Med Sci, Tokyo, Japan
[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA
关键词
genomic imprinting; TS (trophoblastic stem) cells; differentiation; Dnmt3L;
D O I
10.1016/j.ydbio.2006.05.003
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:361 / 373
页数:13
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