Divergent destinies: insights into the molecular mechanisms underlying EPI and PE fate determination

Mammalian pre-implantation development is entirely devoted to the specification of extra-embryonic lineages, which are fundamental for embryo morphogenesis and support. The second fate decision is taken just before implantation, as defined by the epiblast (EPI) and the primitive endoderm (PE) specification. Later, EPI forms the embryo proper and PE contributes to the formation of the yolk sac. The formation of EPI and PE as molecularly and morphologically distinct lineages is the final step of a multistage process, which begins when bipotent progenitor cells diverge into separate fates. Despite advances in uncovering the molecular mechanisms underlying the differential transcriptional patterns that dictate how apparently identical cells make fate decisions and how lineage integrity is maintained, a detailed overview of these mechanisms is still lacking. In this review, we dissect the EPI and PE formation process into four stages (initiation, specification, segregation, and maintenance) and we provide a comprehensive understanding of the molecular mechanisms involved in lineage establishment in the mouse. In addition, we discuss the conservation of key processes in humans, based on the most recent findings.