Understanding size-robust self-organization of morphogen gradients

Lead Research Organisation: UNIVERSITY OF CAMBRIDGE
Department Name: Genetics

Abstract

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Technical Summary

Our textbook understanding of how morphogen gradients form has been challenged by recent research showing that organoids self-organize morphogen gradients despite the absence of external signalling centres thought to be essential for patterning. A striking example is the ability of aggregated embryonic cells to initiate gastrulation in vitro, with the primary body axes forming without maternal cues. In this proposal we combine complementary expertise in mathematical modelling and quantitative experimental approaches to develop a predictive model of this fundamental phenomenon.

We will take two complementary approaches. First, we will study one system in detail, investigating how a Nodal gradient self-organises in aggregates of embryonic zebrafish cells (pescoids), occurring reliably across a range of pescoid sizes. We will model the spatiotemporal dynamics of Nodal ligands, inhibitors and receptors, together with known feedback interactions, iteratively refining the model with quantitative measurements of gene expression and cell movement. We will characterize the robustness of patterning to pescoid size and will test our central hypothesis that cell movement is required for size-robust symmetry breaking.

In parallel, we will build mathematical models of organoids known to break symmetry with distinct signalling pathways and in different morphogenetic contexts. By comparing these models to the size-robust patterning in pescoids, we will investigate why patterning in other organoid systems is often highly sensitive to tissue size and will identify the key parameters that confer size-robustness. A quantitative understanding will enable us to rationally design bioengineering strategies that promote symmetry breaking across a range of organoid sizes. This will inform efforts to improve the reproducibility of organoid culture systems, which often suffer from high error rates compromising their utility as a model for human disease and organ replacement therapies.

Publications

10 25 50
 
Description 1) Development and validation of a method to perform 3D particle image velocimetry (PIV) analysis on multi-view light sheet imaging data.

2) Modelling the morphogenetic processes associated with pescoid symmetry breaking as an active viscous fluid. Generation of testable predictions as to how internalisation and convergence movements synergize to drive morphological symmetry breaking.
Exploitation Route This award is still active and therefore the final outcomes are still in progress.

Based on the outcomes so far, we anticipate that the new methods developed in this award (3D PIV, computational pipeline to simulate reaction-diffusion systems) may be of broad utility, especially in the study of medically relevant organoid systems, both within and outside of academia.
Sectors Healthcare

Manufacturing

including Industrial Biotechology

 
Description Physical modelling of self-organisation in embryonic organoids 
Organisation University of Aberdeen
Department School of Medical Sciences Aberdeen
Country United Kingdom 
Sector Academic/University 
PI Contribution We are responsible for providing experimental data for the collaboration. This involves generating light-sheet imaging datasets and related image analysis to follow the events of symmetry breaking in explants from the zebrafish embryo. We will later perform targeted perturbations to test hypotheses derived from the physical models of the process as developed by our collaborators.
Collaborator Contribution The partners have successfully implemented a 3D model of organoid morphogenesis that will allow for exlporation of the underlying parameter space. This will generate new hypotheses that we aim to test experimentally.
Impact None at present
Start Year 2021