Principles of early human development and germ cell program from conserved model systems

The authors trace the emergence of porcine primordial germ cells and develop in vitro models of primordial germ cell development from human and monkey pluripotent stem cells in order to provide insight into early human development. Mouse embryos develop in an elongated cylinder, whereas human embryos initially form in a flat disc. The flat disc morphology is also observed in pig and monkey embryos, making them more suitable for studying some aspects of development, such as the formation of primordial germ cells (PGCs), the precursors of sperm and eggs. M. Azim Surani and colleagues adopt three approaches to develop useful models of human PGCs. They trace the emergence of PGCs and show that they originate from the posterior epiblast and in response to similar signals and epigenetic changes as seen in human development. Using an in vitro model of PGC development from human and monkey pluripotent stem cells, they demonstrate that a balanced SOX17–BLIMP1 gene dosage is necessary and sufficient for specification of human PGCs from cells in a differentiating embryoid that are at an equivalent stage to the posterior epiblast. Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during weeks 2–3 of early post-implantation development1. Using in vitro models of hPGC induction2,3,4, recent studies have suggested that there are marked mechanistic differences in the specification of human and mouse PGCs5. This may be due in part to the divergence in their pluripotency networks and early post-implantation development6,7,8. As early human embryos are not accessible for direct study, we considered alternatives including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs originate from the posterior pre-primitive-streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. We use this model together with human and monkey in vitro models simulating peri-gastrulation development to show the conserved principles of epiblast development for competency for primordial germ cell fate. This process is followed by initiation of the epigenetic program9,10,11 and regulated by a balanced SOX17–BLIMP1 gene dosage. Our combinatorial approach using human, porcine and monkey in vivo and in vitro models provides synthetic insights into early human development.