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Self-organisation across the scales in early mammalian development

Periodic Reporting for period 3 - SelforganisingEmbryo (Self-organisation across the scales in early mammalian development)

Okres sprawozdawczy: 2020-09-01 do 2021-05-31

A defining feature of living systems is the ability to self-organise form and pattern with function. This project aims to understand the design principle of this multi-cellular self-organisation using early mouse embryos as a model system. In mammals eggs lack polarity and symmetry is broken during early embryogenesis. This results in segregation of the first three cell lineages in the blastocyst. While gene expression changes are extensively studied, how molecular and physical signals are dynamically coupled for self-organised morphogenesis and patterning remains poorly understood. We aim to identify the mechanisms of feedback between cell polarity, mechanics and gene expression across sub-cellular to whole organismal scales that underlie tissue self-organisation. To this end we will adopt an interdisciplinary approach that combines biology, physics and mathematics to measure molecular and physical parameters, build a model integrating them in a reduced system, and quantitatively manipulate the parameters to verify the model. We will build up complexities from the single-cell level to patterning of three cell types with fluid-filled cavities in the mouse blastocyst. This study will set a paradigm for studying multi-cellular self-organisation.
Project 1. Apical domain assembly – self-organisation at the single-cell level

- We have developed an experimental system in which we can study the mechanisms underlying apical domain assembly and the possible role of cortical contractility.

Project 2. Inside-outside patterning – self-organisation at the two-cell level

- We have developed a new reduced experimental system in which to study the role of cell adhesion, contractility and apical domain formation in inside (ICM) – outside (TE) fate specification and patterning.
We are aiming to integrate findings from Project 1 and 2 to prepare a scientific report.

Project 3. Blastocyst patterning – multi-cellular self-organisation with fluid cavities

- We discovered new roles of fluid cavities in the mouse blastocyst: embryo size control and cell fate specification and sorting.
- We showed that interplay between luminal pressure and cell and tissue mechanics controls blastocyst size and call fate. (Chan et al. Nature, accepted in principle)
- We also showed that lumen expansion facilitates cell fate specification and cell sorting in the blastocyst. (Ryan et al. Developmental Cell, in revision)

Project 4. in silico reconstitution and design engineering of the blastocyst

- We have developed an image processing pipeline to automatically track cell lineage and segment cell membrane, in collaboration with the Kreshuk lab (EMBL), to establish the basis for computational analysis and theoretical modeling.
Our model of blastocyst size control (Chan et al. Nature, 2019) introduced a new parameter to the mechanistic model of tissue size and architecture control: luminal pressure. This has a fundamental impact on understanding of morphogenesis and cellular differentiation during development and regeneration in many systems, and we started a number of collaborations to explore general applicability of our model.