HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

Abstract

SUMMARYHuman embryos are often mosaics of diploid and aneuploid cells. We previously modeled elimination of aneuploid cells in pre-implantation mouse embryos using the Mps1 inhibitor reversine. Here, we develop an alternative model using AZ3146, a highly specific Mps1 inhibitor, to determine how aneuploid cells manage to survive within the mosaic embryos. We find that AZ3146 treated embryos overexpress Hypoxia-Inducible-Factor-1A (HIF1A), inhibition of which results in a decreased cell number of extra-embryonic trophectoderm but not embryonic epiblast cells. Hypoxia reduces the levels of DNA damage after either AZ3146 or reversine treatment, inferring a role of HIF1A in DNA repair. To analyze cell competition, we generated aggregation chimeras of DMSO-AZ3146-treated cells (low mosaics) and reversine-AZ3146-treated cells (medium mosaics). Both low and medium chimeras have similar number of cells at the blastocyst stage. However, diploid cells contribute preferentially to epiblast in low mosaics whereas AZ3146-treated cells outcompete reversine-treated cells in all the lineages of medium mosaics. Consistent with its proposed role in aneuploid survival, HIF1A downregulation in mosaic embryos reduces the number of aneuploid cells and favors development of diploid cells. Together these data indicate that diploid cells contribute preferentially to the epiblast and that the survival of aneuploid extra-embryonic cells is promoted by HIF1A.