Abstract
All trophoblast subtypes of the placenta are derived from trophoblast stem cells (TSCs). TSCs have the capacity to self-renew, but how the proliferation of these cells is regulated in the undifferentiated state has been largely unclear. We now show that the F-box protein Skp2 regulates the proliferation of TSCs and thereby plays a pivotal role in placental development in mice on the C57BL/6 background. The placenta of Skp2-/- mouse embryos on the C57BL/6 background was smaller than that of their Skp2+/+ littermates, with the mutant embryos also manifesting intrauterine growth retardation. Although the Skp2-/- mice were born alive, most of them died before postnatal day 21, presumably as a result of placental defects. Depletion of Skp2 in TSCs cultured in the undifferentiated state resulted in a reduced rate of proliferation and arrest of the cell cycle in G1 phase, indicative of a defect in self-renewal capacity. The cell cycle arrest apparent in Skp2-deficient TSCs was reversed by additional ablation of the cyclin-dependent kinase inhibitor (CKI) p57 but not by that of the CKI p27. Our results thus suggest that Skp2-mediated degradation of p57 is an important determinant of the self-renewal capacity of TSCs during placental development, at least in mice of certain genetic backgrounds.