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

Abstract

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during week 2-3 of early postimplantation development1. Using in vitro models of hPGC induction2–4, recent studies suggest striking mechanistic differences in specification of human and mouse PGCs5. This may partly be due to the divergence in their pluripotency networks, and early postimplantation development6–8. Since early human embryos are inaccessible for direct studies, we considered alternatives, including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs (pPGCs) originate from the posterior pre-primitive streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. Together with human and monkey in vitro models simulating peri-gastrulation development, we show conserved principles for epiblast development for competency for PGC fate, followed by initiation of the epigenetic programme9–11, 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 on early human development.

On the origin of the human germline

“…To investigate the mechanisms underlying hPGC specification in greater detail, we have recently developed in vitro models using human pluripotent stem cells (hPSCs), which are considered to be equivalent to early postimplantation epiblast cells, in an attempt to mimic posterior epiblast development during gastrulation Kobayashi et al, 2017). These in vitro models identified SOX17 as a crucial specifier of hPGC fate, confirming our initial findings .…”

Signals and transcription factors for specification of human germ cells

“…Peak of competence for hPGC fate was acquired 12 hours during mesendoderm differentiation, at which cells showed moderate expression of primitive streak markers (e.g., EOMES, T) (10). At later time points competence for hPGC fate declined and mesoderm or endoderm fate was induced (10). More detailed analysis using single factor approaches showed that SOX17 alone was able to induce hPGC fate from ESCs, but SOX17 and BLIMP1 together were able to induce hPGC competence more robustly and rapidly (10).…”

“…Based on these results, Kobayashi et al then investigated the induction potential of hPGCs from pluripotent stem cells over the time course of mesendodermal differentiation (10). Peak of competence for hPGC fate was acquired 12 hours during mesendoderm differentiation, at which cells showed moderate expression of primitive streak markers (e.g., EOMES, T) (10).…”

Evolutionarily diverse mechanisms of germline specification among mammals: what about us?

“…Then, SOX17, PRDM1, and TFAP2C together promote the germline specification program, apparently without strictly requiring PRDM14 (19). An independent study performed by the group of Surani indicates that balanced expression of SOX17 and PRDM1 seems important for specification of human PGCLCs (5).…”

“…Only recently, information on the cynomolgus monkeys (a.k.a. crab-eating macaque or long-tailed macaque) (3), rhesus monkeys (4), and pigs (5) has been made available. At embryonic day (E) 6.0-6.5 of egg-cylinder-shaped mouse embryos, six PGC precursors are located in the most proximal region of the post-implantation and pre-gastrulation epiblast, close to the extra-embryonic tissues and the region where primitive streak will be formed.…”