A close look at the mammalian blastocyst: epiblast and primitive endoderm formation

Abstract

During early development, the mammalian embryo undergoes a series of profound changes that lead to the formation of two extraembryonic tissues--the trophectoderm and the primitive endoderm. These tissues encapsulate the pluripotent epiblast at the time of implantation. The current model proposes that the formation of these lineages results from two consecutive binary cell fate decisions. The first controls the formation of the trophectoderm and the inner cell mass, and the second controls the formation of the primitive endoderm and the epiblast within the inner cell mass. While early mammalian embryos develop with extensive plasticity, the embryonic pattern prior to implantation is remarkably reproducible. Here, we review the molecular mechanisms driving the cell fate decision between primitive endoderm and epiblast in the mouse embryo and integrate data from recent studies into the current model of the molecular network regulating the segregation between these lineages and their subsequent differentiation.

Fig. 1

Schematic representation of early mouse embryonic development. The scheme depicts embryonic development starting from the compacted eight-cell stage (2.5 days post-fertilization) to the implanting blastocyst (4.5 days post-fertilization). Starting from the eight-cell stage, the orientation of the plane of cleavage will be important in the generation of inside ICM (grey) and outside trophectoderm (green) cells. While symmetric division (purple) will generate two outside cells, asymmetric division (orange) will generate one inside and one outside cell. Subsequently, ICM cells will differentiate into the Epi (red) and PrE (blue)

Fig. 2

Modeling PrE and EPI cell fate decision in wild-type and mutant contexts. The scheme depicts PrE (blue) and Epi (red) formation starting from unspecified ICM cells (grey) to a determined state. In wild-type embryos, unspecified ICM cells have already initiated both PrE and Epi genetic programs (visualized by the expression of NANOG and GATA6). Through positive and negative regulation (that might be direct or indirect), a cell fated to become Epi will secrete FGF4 ligand, which will instruct an adjacent cell to become PrE, through a signaling cascade involving FGFR2, ERK, and OCT4. PrE progenitors will turn off Epi genetic programs and will mature through the expression of SOX17 and GATA4. In the absence of Fgf4, ICM cells cannot be instructed to become PrE and by default mature to Epi cells. In the absence of Nanog, ICM cells cannot mature to Epi fate and consequently do not secrete FGF4 to instruct cells to become PrE. ICM cells can form intermediate PrE progenitors but these progenitors cannot mature. In absence of Oct4, the signal transduction cascade between FGFR and the regulation of PrE transcriptional program is impaired. Epi cells are formed but PrE progenitors do not properly mature and acquire an undetermined identity (brown). Changes in the size of the letters and the arrows indicate changes in the levels of proteins and the regulation loops