Resumen de Evolution of embryonic pluripotency
Beatriz Fernández-Tresguerres Torrecillas
Pluripotency in the early mouse is established and maintained by a gene regulatory network under the control of a core set of transcription factors that includes Oct4, Sox2 and Nanog. This network is shared by the embryonic stem cells which can give rise to any adult cell type thanks in part to this network, which shuts down the cells' differentiation programs and keeps them in an undifferentiated state. While the network is largely conserved in eutherian mammals, very little information is available regarding its evolutionary conservation in other vertebrates. We have compared the embryonic pluripotency networks in mouse and chick by means of expression analysis in the pre-gastrulation chick embryo, genomic comparisons, functional assays of pluripotency-related regulatory elements in ES cells and blastocysts, and in vivo overexpression assays. We find that multiple components of the network are either novel to mammals or have acquired novel expression domains in early developmental stages of the mouse. We also find that the downstream action of the mouse core pluripotency factors is largely mediated by genomic sequence elements that are not conserved with chick. In the case of Sox2 and Fgf4, we find that elements driving expression in embryonic pluripotent cells have evolved through a small number of nucleotide changes that created novel binding sites for core factors.
These findings suggest that the EP-GRN arose not only through the appearance of novel pluripotency genes but also by co-opting and duplicating existing genes and establishing new regulatory interactions between them. The de novo appearance of some of these interactions in mammals was confirmed by overexpressing Nanog in chick and mouse embryos. Furthermore, expression analysis of these embryos suggests additional conserved roles for Nanog as a repressor of neural and haematopoietic differentiation at gastrulation stages.
Our results show that the network in charge of embryonic pluripotency is an evolutionary novelty of mammals that may have evolved owing to the comparatively extended period during which mammalian embryonic cells need to be maintained in an undetermined state prior to differentiation. Further knowledge of how this embryonic pluripotency changed during evolution will provide a deeper understanding of its control and it will extend our ability to exploit the potential of stem cells.
