Abstract
Primordial germ cell (PGC) specification is the first step in the development of the germline. Recent work has elucidated human-mouse differences in PGC differentiation and identified cell states with enhanced competency for PGC-like cell (PGCLC) differentiation in vitro in both species. However, it remains a subject of debate how different PGC competent states in vitro relate to each other, to embryonic development, and to the origin of PGCs in vivo. Here we review recent literature on human PGCLC differentiation in the context of mouse and non-human primate models. In contrast to what was previously thought, recent work suggests human pluripotent stem cells (hPSCs) are highly germline competent. We argue that paradoxical observations regarding the origin and signaling requirements of hPGCLCs may be due to local cell interactions. These confound assays of competence by generating endogenous signaling gradients and spatially modulating the ability to receive exogenous inductive signals. Furthermore, combinatorial signaling suggests that there is no unique germline competent state: rather than a one-dimensional spectrum of developmental progression, competence should be considered in a higher dimensional landscape of cell states.