Hiiragi Group

Looking at the molecular, cellular and systems levels, the Hiiragi group studies how, early in mammal development, the embryo is shaped from a spherical mass of cells.

Previous and current research

A fundamental question in developmental biology is the mechanism by which the embryonic asymmetry is established during development. Early mammalian development is characterised by formation of the embryonic polarity and initial cell lineages in the blastocyst, composed of the inner cell mass (ICM) surrounded by one-cell layer of the trophectoderm (TE). The former lineage generates the embryo proper, while the latter yields an extra-embryonic tissue specific to mammals, the placenta. Despite its importance for understanding mammalian development and for stem cell research, the molecular mechanism of blastocyst patterning has long been elusive. How is the symmetry broken in the mammalian embryo? How is the definitive embryonic pattern established?

We have developed a live-imaging system for mouse pre-implantation embryos, demonstrating unexpectedly high dynamicity during early morphogenesis. Our studies characterised key principles underlying early mammalian development: absence of polarity in the egg, and localised determinants play little or no role in generating the asymmetry (Figure 1);stochastic processes generate dynamic heterogeneity (Figure 2); mechanical and structural context plays a key role (Figure 3).

Collectively, an attractive hypothesis is that early mammalian embryogenesis may be to some extent a stochastic process in a particular structural context that eventually leads to self-organisation.

These features suggest that, in order to fully understand the mechanisms of early mammalian development, it will be essential to address how the diverse inputs acting on every individual cells are integrated in the embryo at the systems level. Thus we have recently established necessary tools and multi-disciplinary strategies: a fluorescence-based gene-trap mouse lines that visualise molecular dynamics during embryonic patterning; gene expression profile of every single cells in the mouse pre-implantation embryo; computer simulation of the blastocyst morphogenesis (Figure 3).

Mouse pre-implantation embryo is suitable for the systems-level study, because it is an isolated system, composed of a limited number of cells (up to 64) and of cell populations (four); the development can be recapitulated in vitro and be visualised by live-imaging; and micro-manipulation is applicable. We aim at understanding general principles and robustness underlying early mammalian development.

Future projects and goals

We adopt a wide variety of experimental strategies including molecular genetics, live-imaging, cell physics, and modelling, to address fundamental questions in development and cell biology at a molecular, cellular and systems levels. Our goals are:

• identification of the symmetry breaking cue in the mouse embryo
• understanding the molecular mechanism leading to the first lineage establishment
• 4D imaging microscopy to digitally reconstruct embryogenesis
• evaluating the significance of dynamic molecular heterogeneity.