Evidence implicating sequential commitment of the founder lineages in the human blastocyst by order of hypoblast gene activation

Successful human pregnancy depends upon rapid establishment of three founder lineages: trophectoderm, epiblast and hypoblast, which together form the blastocyst. Each plays an essential role in preparing the embryo for implantation and subsequent development. Several models are proposed to define the lineage segregation. The first suggests that all specify simultaneously; the second favours differentiation of trophectoderm before separation of epiblast and hypoblast, either via differentiation of hypoblast from established epiblast, or production of both tissues from the inner cell mass precursor. To begin to resolve this discrepancy and thereby understand the sequential process for production of viable human embryos, we investigated the expression order of genes associated with emergence of hypoblast. Based upon published data and immunofluorescence analysis for candidate genes, we present a basic blueprint for human hypoblast differentiation, lending support to the proposed model of sequential segregation of the founder lineages of the human blastocyst. The first characterised marker, specific initially to the early inner cell mass, and subsequently identifying presumptive hypoblast is PDGFRA, followed by SOX17, FOXA2 and GATA4 in sequence as the hypoblast becomes committed. Summary Statement Optimal segregation of human blastocyst founder lineages is essential to establish healthy human pregnancies. Mapping activation of hypoblast marker genes over time helps understand how the yolk sac is regulated.