Systems-level understanding of early mammalian development
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.
Figure 1: Unprecedented molecular heterogeneity during mouse blastocyst patterning. Cells expressing Nanog (green), Gata6 (red) or Serpinh1 (blue).
Figure 2: Microtubules (green) self-assemble into a mitotic spindle from multiple microtubule-organising centres (red) in the absence of centriole, during progressive transition from meiosis to mitosis in early mouse development.
Previous and current research
A fundamental question in biology is the mechanism by which the embryonic asymmetry is established during development. In contrast to many organisms in which embryonic development is driven by determinants localised asymmetrically in the egg, mammalian eggs lack polarity and thus symmetry has to be broken during early embryogenesis. This symmetry breaking process in mammalian embryos results in the formation of the blastocyst, composed of the inner cell mass surrounded by the trophectoderm. Despite its importance, 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, stochasticity and molecular heterogeneity (figure 1) during early embryogenesis. Our recent study also demonstrated that centriole is generated de novo during the gradual transition from meiosis to mitosis at the pre-implantation stage (figure 2). Taken together, and in light of its highly regulative capacity, early mammalian embryo may be viewed as a self-organising system, patterning through stochastic processes in a particular structural context. 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 individual cells are integrated in the embryo at the systems level. Thus we have recently established necessary tools and multi-disciplinary strategies, including fluorescence gene-trap mice that allow quantitative characterisation of gene-expression dynamics, and mapping of cellular mechanical properties during morphogenesis. Furthermore, our recent single-cell transcriptome analysis led us to propose a new model for symmetry breaking during embryogenesis, in which stochastic cell-to-cell gene expression variability followed by signal reinforcement progressively and antagonistically segregate lineages within initially equivalent cells.
Overall we aim at understanding principles and robustness underlying early mammalian development.
Future projects and goals
We adopt a wide variety of experimental strategies including embryology, molecular genetics, live-imaging, cell physics and modelling in order to address fundamental questions in development and cell biology at a molecular, cellular and systems level. Our goals include:
- identification of the symmetry-breaking cue in the mouse embryo;
- investigating the significance of molecular heterogeneity in lineage segregation;
- understanding the role of mechanical cues in embryogenesis;
- identification of the trigger and mechanism for centriole biogenesis in vivo.