Figure 1: Molecular heterogeneity during mouse blastocyst patterning. Cells expressing Nanog (green), Gata6 (red) or Serpinh1 (blue).
Figure 2: Mapping of surface tensions in a developing mouse embryo.
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
Mammalian development begins with cells that are equivalent in their position and developmental potential. This initial symmetry among cells is broken during development to form the blastocyst consisting of two major cell types, the inner cell mass and trophectoderm, which are distinct in their position and gene expression. Recent studies unexpectedly revealed that morphogenesis and gene expression is highly dynamic and stochastic during this process (Figure 1). Determining which signal breaks the initial symmetry and how stochastic gene expression leads to the reproducibly patterned blastocyst remain fundamental open questions about the beginning of mammalian life.
We have developed new imaging and experimental systems to monitor early mouse development at unprecedented spatio-temporal resolution. Using genetics, high-resolution microscopy and computational analysis, we established the complete map of mouse pre-implantation development and identified the precise moment of symmetry breaking. This breakthrough now provides the basis to investigate the cellular and molecular mechanism of symmetry breaking.
Upon symmetry-breaking, gene expression varies stochastically between cells before it progressively stabilises into a reproducible pattern segregating the first lineages of the blastocyst. This self-organizing process likely relies on feedbacks between gene regulatory networks and cell and tissue mechanics to achieve a coordinated developmental program. To understand how the tissue architecture regulates cell fate specification, we study the mechanical properties of cells that shape the embryo. Using a non-invasive micropipette aspiration method, we map the surface tensions of cells in space and time within the developing mouse embryo (Figure 2). An integrative understanding based on the complete maps of cell lineage, gene expression and cell mechanics allows prediction and testing of our models.
Future projects and goals
We adopt a wide variety of experimental strategies including embryology, molecular genetics, live-imaging, biophysics and theoretical 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 mammalian embryos;
- molecular characterisation of the de novo formation of epithelial polarity;
- understanding the interplay between cell mechanics and genetics during self-organisation;
- identification of the trigger and mechanism for centriole biogenesis in vivo.