Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells

被引:215
作者
Parisi, T
Beck, AR
Rougier, N
McNeil, T
Lucian, L
Werb, Z
Amati, B
机构
[1] DNAX Res Inst Mol & Cellular Biol Inc, Palo Alto, CA 94304 USA
[2] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[3] ETH Honggerberg HPT, Inst Biotechnol, CH-8093 Zurich, Switzerland
[4] European Inst Oncol, Dept Expt Oncol, I-20141 Milan, Italy
关键词
cell cycle; cyclin E; endoreplication; placenta; trophoblast;
D O I
10.1093/emboj/cdg482
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In mammalian cells, cyclin E-CDK2 complexes are activated in the late G(1) phase of the cell cycle and are believed to have an essential role in promoting S-phase entry. We have targeted the murine genes CCNE1 and CCNE2, encoding cyclins E1 and E2. Whereas single knockout mice were viable, double knockout embryos died around midgestation. Strikingly, however, these embryos showed no overt defects in cell proliferation. Instead, we observed developmental phenotypes consistent with placental dysfunction. Mutant placentas had an overall normal structure, but the nuclei of trophoblast giant cells, which normally undergo endoreplication and reach elevated ploidies, showed a marked reduction in DNA content. We derived trophoblast stem cells from double knockout E3.5 blastocysts. These cells retained the ability to differentiate into giant cells in vitro, but were unable to undergo multiple rounds of DNA synthesis, demonstrating that the lack of endoreplication was a cell-autonomous defect. Thus, during embryonic development, the needs for E-type cyclins can be overcome in mitotic cycles but not in endoreplicating cells.
引用
收藏
页码:4794 / 4803
页数:10
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