Research reveals the mechanisms that guide the fate of individual embryonic cells

The fusion of a sperm and egg yields a zygote with an unconstrained capacity to develop into any cell type in the body. Subsequent rounds of cell division limit those options as the embryo enters a developmental program that establishes the formation of tissues, organs and limbs.

By profiling gene expression in individual cells at the earliest stages of mouse development, Ernesto Guccione of the A*STAR Institute of Molecular and Cell Biology in Singapore and Maria-Elena Torres-Padilla of the University of Strasbourg in France have zoomed in on events that help to initiate this process when the embryo consists of just four cells1.

Two classes of proteins are known to help coordinate cellular development; transcription factors bind DNA to modulate gene expression while epigenetic modifiers act indirectly by adding and removing chemical marks from chromosomes that stimulate or inhibit gene activity. "This reprogramming occurs at a single-cell level so it is critical to study these events not in cell populations, such as entire embryos, but with techniques that allow us to distinguish which cell is which," says Guccione.

Guccione and Torres-Padilla wanted to understand how cells 'decide' to form either the inner cell mass (ICM), which gives rise to the embryo itself, or the trophectoderm (TE), which forms tissues that support the embryo. They dissected mouse embryos at multiple developmental stages and profiled transcription factors and epigenetic modifiers within individual cells.

Previous studies have defined the ICM and TE based on the activity of specific transcription factors. However, the researchers were surprised to find that the earliest developmental stages are primarily characterized by shifts in the activity of epigenetic modifiers. This is the case until the embryo consists of 32 cells—at which point both the TE and ICM are clearly defined. Computational modeling suggests that the stepwise action of these epigenetic modifiers essentially creates a developmental 'track' for the early embryo.

One modifier, PRDM14, was especially active in ICM cells (see image), and influences cellular fate very early in development. "We showed that PRDM14 is expressed in only two cells at the four-cell stage," says Guccione, "and proved that it plays a role in driving cells towards the ICM fate as opposed to the TE." Indeed, injecting PRDM14 into two-cell embryos notably 'tipped the scales' to favor ICM formation. Guccione notes that this protein can both activate and repress target genes, and deciphering its role in ICM development is a future priority for his group.