A self-organization framework for symmetry breaking in the mammalian embryo.

The mechanisms underlying the appearance of asymmetry between cells in the early embryo and consequently the specification of distinct cell lineages during mammalian development remain elusive. Recent experimental advances have revealed unexpected dynamics of and new complexity in this process. These findings can be integrated in a new unified framework that regards the early mammalian embryo as a self-organizing system.

Venus trap in the mouse embryo reveals distinct molecular dynamics underlying specification of first embryonic lineages.

Mammalian development begins with the segregation of embryonic and extra-embryonic lineages in the blastocyst. Recent studies revealed cell-to-cell gene expression heterogeneity and dynamic cell rearrangements during mouse blastocyst formation. Thus, mechanistic understanding of lineage specification requires quantitative description of gene expression dynamics at a single-cell resolution in living embryos. However, only a few fluorescent gene expression reporter mice are available and quantitative live image analysis is limited so far. Here, we carried out a fluorescence gene-trap screen and established reporter mice expressing Venus specifically in the first lineages. Lineage tracking, quantitative gene expression and cell position analyses allowed us to build a comprehensive lineage map of mouse pre-implantation development. Our systematic analysis revealed that, contrary to the available models, the timing and mechanism of lineage specification may be distinct between the trophectoderm and the inner cell mass. While expression of our trophectoderm-specific lineage marker is upregulated in outside cells upon asymmetric divisions at 8- and 16-cell stages, the inside-specific upregulation of the inner-cell-mass marker only becomes evident at the 64-cell stage. This study thus provides a framework toward systems-level understanding of embryogenesis marked by high dynamicity and stochastic variability.

Stochastic processes in the development of pluripotency in vivo.

The divergence of the pluripotent inner cell mass and extraembryonic trophectoderm from an apparently homogenous population of cells is a decisive event in mammalian preimplantation development. While three models have been proposed to explain early cellular differentiation in the mouse embryo, the initial cue generating asymmetry within the embryo remains elusive. Recently, unexpected heterogeneity in the expression of crucial transcription factors within the blastocyst has raised the intriguing possibility that a stochastic component is involved in lineage divergence. Unraveling the molecular dynamics and developmental function of the observed heterogeneity awaits further investigations at the single-cell level using quantitative live-imaging with appropriate reporter lines. The possible involvement of dynamic heterogeneity in the establishment, maintenance and resolution of pluripotency makes this topic highly relevant not only to developmental biology, but also to stem cell research and regenerative medicine. In this review, we discuss the possible involvement of stochastic processes in lineage divergence and the establishment of pluripotency in vivo, based on recent data from mouse embryology and stem cell research.