Figure 1: Symmetry breaking in the mouse embryo at the 8-cell stage (the emerging apical domain marked with Ezrin, red; Actin, green).

Figure 1: Symmetry breaking in the mouse embryo at the 8-cell stage (the emerging apical domain marked with Ezrin, red; Actin, green).

Figure 2: Molecular heterogeneity during mouse blastocyst patterning. Cells expressing Nanog (green), Gata6 (red) or Serpinh1 (blue).

Figure 2: Molecular heterogeneity during mouse blastocyst patterning. Cells expressing Nanog (green), Gata6 (red) or Serpinh1 (blue).

The Hiiragi group studies early mammalian development at the molecular, cellular and systems levels to elucidate how an intricate embryo emerges from a spherical mass of cells.

Previous and current research

A defining feature of multi-cellular living systems is the capacity to break symmetry and generate well-defined forms and patterns through self-organisation. Our group aims to understand the design principle of multi-cellular self-organisation, using a well-suited model system: early mouse embryos. Mammalian eggs lack polarity and thus symmetry is broken during early embryogenesis (figure 1). This symmetry breaking results in the formation of a blastocyst consisting of two major cell types, the inner cell mass and the trophectoderm, each distinct in its position and gene expression profile. Recent studies unexpectedly revealed that morphogenesis and gene expression are highly dynamic and stochastically variable during this process (figure 2). Determining which signal breaks the initial symmetry and how the blastocyst establishes a remarkably reproducible shape and pattern despite the preceding variability remain fundamental open questions about the beginning of mammalian life (Wennekamp et al. 2013).

Our recent studies led us to the working hypothesis that feedback interactions between cell and tissue mechanics (contractility, adhesion, geometry and pressure), cell polarity and cell fate may be central components of multi-cellular self-organisation (Korotkevich et al. 2017; Maitre et al. 2016). We aim to understand how molecular, cellular and physical signals are dynamically coupled across the scales for self-organisation during early mammalian development.

To this end, we have developed a unique set of experimental frameworks that integrate biology and physics. Firstly, we apply advanced live-embryo imaging and comprehensive lineage mapping to monitor early embryogenesis at unprecedented spatio-temporal resolution (Dietrich, Panavaite et al. 2015; Strnad et al. 2016). Secondly, we design and utilise reduced experimental systems to decouple and measure interdependent parameters acting on developing embryos and build physical models (Korotkevich et al. 2017; Maitre et al. 2015; Maitre et al. 2016). Thirdly, we use genetics, biophysics and micromanipulation to spatio-temporally control the system and test predictions of our models (Korotkevich et al. 2017; Maitre et al. 2016).

Using early mammalian embryos we aim to set a paradigm for studying self-organisation across subcellular, cellular and whole organismal scales.

Future projects and goals

We adopt a wide variety of experimental strategies including embryology, genetics, advanced microscopy, biophysics and theoretical modelling in order to address fundamental questions in development and cell biology at molecular, cellular and systems levels. Our goals include:

  • Understanding the symmetry-breaking mechanism in mammalian embryos.
  • Molecular characterisation of the de novo formation of cell polarity.
  • Understanding the feedback mechanisms between cell and tissue mechanics, cell polarity and fate specification.
ERC INVESTIGATOR