Hiiragi: Multi-cellular coordination

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The Hiiragi group studies robustness in development and aims to understand the design principle of self-organising multi-cellular systems.

Self-organisation is a defining feature of living systems and entails complex interplay between molecular, cellular and mechanical signals across various spatio-temporal scales. Using early mammalian embryos as a model, the Hiiragi group adopts a variety of methods including genetics, microscopy, biophysics, engineering and modelling, to investigate how self-organised forms and patterns emerge from a spherical mass of cells.

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

Self-organisation in context

Mammalian eggs lack polarity and symmetry is broken during early embryogenesis. Our studies revealed that morphogenesis and gene expression are highly variable between embryos and cells during this period (Dietrich et al. 2007 Development; Ohnishi et al. 2014 Nat Cell Biol; Niwayama et al. 2019 Dev Cell). Determining how early embryos develop with reproducible form despite such variability remains a fundamental question in mammalian development. We established a multi-disciplinary framework integrating biology, physics and mathematics, which showed that feedback interactions between cell and tissue mechanics (contractility, adhesion, geometry and pressure), polarity, and fate robustly control size and inside-outside patterning of the early mouse embryo (Korotkevich et al. 2017 Dev Cell; Maître et al. 2016 Nature; Chan et al. 2019 Nature; supported by ERC AdG SelforganisingEmbryo). We will build on our mechanistic understanding, and integrate the self-organisation model to tissue-tissue and embryo-uterus interactions that were revealed by our recent study (Ichikawa, Zhang, Panavaite et al. 2022 Dev Cell; Bondarenko et al. 2023 EMBO J).

Cellular dynamics revealed by a new ex vivo culture system and automatic image analysis

Embryo size control

The size of embryos and their organs is precisely controlled in each species, despite the inherent variabilities observed during morphogenesis and growth. The previously reported mechanism for embryo size control (Chan et al. 2019 Nature) works only when fluid cavity expansion is substantially faster than tissue growth, as in pre-implantation embryos. However, the mechanism underlying the remarkable precision in post-implantation growth remains unknown. Using our newly developed ex vivo culture systems (Ichikawa, Zhang, Panavaite et al. 2022 Dev Cell; Bondarenko et al. 2023 EMBO J), we will dissect the dynamic changes in cell and tissue growth. We aim to understand how the size of tissues and embryos are sensed, and how this feeds back into the system to control cellular growth dynamics.

Mouse embryo implanting into the uterine tissue

Coordination in space and time

The developmental programme operates in space and time. While we are beginning to understand the mechanisms of spatial coordination of development within the framework of morphogenesis, little is known about how developmental progression is temporally controlled. Furthermore, the relationship between spatial and temporal programmes for developmental precision is yet to be explored. On one hand, our recent study showed a new role for temporal variability in cell cycle progression during robust embryo patterning (Fabrèges, bioRxiv). On the other hand, embryo size may be adjusted by sensing the spatial dimensions of the embryo and changing cell cycle dynamics accordingly. We will use cell and embryo size control as a paradigm to study the coordination of developmental programmes in space and time (supported by ERC AdG COORDINATION, 2023-2028).