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  • The EMBO Journal (2003) 22, 4794 - 4803
  • doi:10.1093/emboj/cdg482

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

Tiziana Parisi1, Andreas R. Beck2, Nathalie Rougier3, Tom McNeil1, Linda Lucian1, Zena Werb3 and Bruno Amati1,4

  1. DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304, USA
  2. Institute of Biotechnology, ETH Hönggerberg HPT, CH-8093 Zürich, Switzerland
  3. Department of Anatomy, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA
  4. Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, I-20141 Milan, Italy

Correspondence to:

Bruno Amati, E-mail: bruno.amati@ieo-research.it

Received 11 July 2003; Accepted 1 August 2003

In mammalian cells, cyclin E–CDK2 complexes are activated in the late G1 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.

  • Keywords:

    • cell cycle,
    • cyclin E,
    • endoreplication,
    • placenta,
    • trophoblast