Loss of the maternal imprint in Dnmt3Lmat-/- mice leads to a differentiation defect in the extraembryonic tissue.
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 (Dnmt3L(mat-/-)) 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.
Arima
Takahiro
T
Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Medical Institute of Bioregulation, Kyusyu University, Beppu, Oita 874-0838, Japan. tarima@tsurumi.beppu.kyushu-u.ac.jp
Hata
Kenichiro
K
Tanaka
Satoshi
S
Kusumi
Maki
M
Li
En
E
Kato
Kiyoko
K
Shiota
Kunio
K
Sasaki
Hiroyuki
H
Wake
Norio
N
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010920:Placenta / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D014327:Trophoblasts / Q000378:metabolism
C498796:Dnmt3l protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases