Abstract
Murine development demands that pluripotent epiblast stem cells in the peri-implantation embryo increase from approximately 120 to 14,000 cells between embryonic days (E) 4.5 and E7.5. This is possible because epiblast stem cells can complete cell cycles in under 3 h in vivo. To ensure conceptus fitness, epiblast cells must undertake this proliferative feat while maintaining genome integrity. How epiblast cells maintain genome health under such an immense proliferation demand remains unclear. To illuminate the contribution of genome stability pathways to early mammalian development we systematically reviewed knockout mouse data from 347 DDR and repair associated genes. Cumulatively, the data indicate that while many DNA repair functions are dispensable in embryogenesis, genes encoding replication stress response and homology directed repair factors are essential specifically during the peri-implantation stage of early development. We discuss the significance of these findings in the context of the unique proliferative demands placed on pluripotent epiblast stem cells.
Highlights
OverviewPluripotent cells in early mammalian embryos proliferate at a phenomenal rate
Within Mouse Genome Informatics Gene Ontology Project (MGI-GO) we identified 347 genes grouped within the ontologies of major DNA repair pathways (MGI-GO designations: DNA damage checkpoint, nucleotide excision repair, mismatch repair, base excision repair, homologous recombination, and non-homologous end joining)
Essential Roles for homology directed repair (HDR) Factors During Peri-Implantation. It is possible the canonical G1-phase Classical non-homologous end joining (c-NHEJ) double strand breaks (DSBs) repair pathway is dispensable during peri-implantation because cells rapidly transition through their brief G1 phase and engage alt-NHEJ or HDR in S-phase
Summary
Pluripotent cells in early mammalian embryos proliferate at a phenomenal rate. This is necessary to maintain embryo growth and reach critical developmental milestones within defined temporal windows. Most of the targeted genes that conferred embryonic lethality, 62 genes, did so during the period of rapid cell proliferation occurring with peri-implantation development (E4.5 to E8.5) (Table 2). Peri-implantation development is associated with exceptionally rapid cell proliferation during “gastrulation,” which begins at E5.5 as the embryo elongates and a luminal pro-amniotic cavity opens in the center of the epiblast cell mass (Snow, 1976). Totipotent cells are present in the embryo between fertilization and morula formation They can give rise to any cell type from any stage of the animal’s life, including germ and placental cells. Pluripotent cells exist in the inner cell mass (ICM) and epiblast region of the developing embryo from the blastocyst stage to immediately prior to organogenesis. Multipotent cells exist in newly formed tissues or organs and can develop into a limited number of cell types within their original dermal lineage
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