期刊
EMBO JOURNAL
卷 22, 期 18, 页码 4794-4803出版社
WILEY
DOI: 10.1093/emboj/cdg482
关键词
cell cycle; cyclin E; endoreplication; placenta; trophoblast
资金
- NCI NIH HHS [CA72006, P01 CA072006] Funding Source: Medline
- NIA NIH HHS [AG23218, R01 AG023218] Funding Source: Medline
- NICHD NIH HHS [HD26732] Funding Source: Medline
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.
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