Functional and mechanistic characterization of Foxd3 during mouse peri-implantation transitions.

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Following implantation, epiblast cells within the mouse embryo undergo a critical cell fate decision, becoming specified towards either the perishable soma or the immortal germline. The pre-implantation epiblast displays naïve pluripotency and can give rise to all embryonic lineages. Upon implantation, the epiblast transits to a primed state, characterized by the loss of naïve pluripotency and the incipient expression of somatic genes. A few post-implantation epiblast cells are able to revert somatic differentiation and undergo major reprogramming events leading to germline specification. Using mouse embryonic stem cells as an in vitro differentiation model, we recently uncovered Foxd3 as a novel regulator that promotes the transition from naïve to primed pluripotency and, subsequently, prevents the acquisition of germline identity. Mechanistically, Foxd3 acts as a transcriptional repressor that decommissions enhancers necessary for the expression of key naïve pluripotency and germline genes. However, the in vivo relevance and evolutionary conservation of Foxd3 function during peri-implantation development are currently unknown. Here we propose a number of experiments that should provide mechanistic and functional insights into the role of Foxd3 in the post-implantation primed epiblast. We hypothesize that Foxd3 can act as a major epiblast patterning regulator conferring anterior identity. Using both in vitro and in vivo models, we will test whether this novel Foxd3 function is evolutionary conserved. Furthermore, we have previously shown in vitro that the silencing of Foxd3 is a critical regulatory event during the specification of mouse primordial germ cells (PGCs). In the current proposal, we will determine if this silencing event is equally important for in vivo germline specification and whether it is also relevant in humans. Overall, our work should provide a deeper understanding of the molecular mechanisms orchestrating peri-implantation development, which could help improving the in vitro derivation of PGCs and gametes and potentially opening new possibilities for the treatment of infertility.