p53-mediated regulation of epiblast cell numbers predicts reactivation during mouse embryonic diapause

Embryonic diapause is a temporary suspension of proliferation in mammalian pre-implantation embryos, allowing for reactivation later. Cells in mouse diapause embryos enter the G0 phase within 7 days of diapause initiation. Here, we show that approximately 5% of cells in embryonic tissues continue to proliferate even after 7 days of diapause. Transcriptome and phenotypic analyses reveal that p53 facilitated DNA damage repair via p21-mediated cell cycle arrest and regulated epiblast cell numbers via Bax-mediated apoptosis. Moreover, epiblast cell numbers strongly correlated with reactivation rates, with deviations from optimal levels impairing successful reactivation. Our findings call into question the conventional view that all cells in diapause embryos uniformly enter G0. We established epiblast characteristics as predictive factors for determining reactivation success, the defining event of diapause.