Systems-level understanding of early mammalian development
Figure 1: Unprecedented molecular heterogeneity during mouse blastocyst patterning. Cells expressing Nanog (green), Cdx2 (red) or both (yellow)
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
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 biology is the mechanism by which 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. In view of this and its highly regulative capacity, the early mammalian embryo may be 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 to investigate this: fluorescence-based gene-trap mice that allow quantitative characterisation of molecular dynamics; transcriptomics of every single cell in the embryo; computer simulation of the blastocyst morphogenesis.
In the early mouse embryo the spindle is self-assembled from randomly distributed microtubule-organising centres in the absence of centriole. Our recent study demonstrated a surprising gradual transition from meiosis to mitosis over the pre-implantation stage (figure 2), during which centriole is generated de novo without template. We use this unique and effective system to study the mechanism of centriole biogenesis in vivo.
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 are:
- identification of the symmetry breaking cue in the mouse embryo
- understanding the molecular mechanisms leading to the first lineage specification
- investigating the role of molecular heterogeneity in lineage segregation
- identification of the essential molecule and trigger for centriole biogenesis.