CORDIS - EU research results

Molecular origin and function of dynamic heterogeneities in mouse ES cells and pre-implantation embryos

Final Report Summary - MOFDH (Molecular origin and function of dynamic heterogeneities in mouse ES cells and pre-implantation embryos)

Over the last few years it has become apparent that within a population of seemingly identical cells in a similar developmental state, there is a large degree of variability in the expression of the same genes from one cell to another. This variability results in heterogeneities in gene expression which can be measured and emerge as representative of specific states. These heterogeneities are more evident when cells change state which has led to the proposal that they might be under control, and be associated with decision making during fate transitions by creating a substrate for the decision.

Over the course of the project, using mouse Embryonic Stem cells as a model system, we have shown that gene expression heterogeneities have a dynamics and result in stable gene specific distributions i.e. the heterogeneities are homeostatic. Through a combination of experiments and modelling, we have shown that extracellular signals, and in particular Wnt signalling, regulate the parameters of these gene specific distributions. When cells change state, for example during differentiation, the control over the distribution results in the number of cells adopting a new fate. We have tested this hypothesis using the differentiation of ES cells in adherent culture and their first fate choice into neural or endomesodermal and shown that, indeed, Wnt signalling contributes to the dynamics of the event rather than to the fate of the cells.

Experiments in non adherent culture led to the remarkable observation that when a critical number of cells (normally around 300) are brought together and set to differentiate, they undergo symmetry breaking events, axial organization and growth much in the manner that embryos do. These aggregates, that we have called gastruloids, undergo a process very similar to gastrulation and organize themselves with anteroposterior and dorsoventral bilaterally symmetric axes; recently we have also observed that they exhibit a Left/Right asymmetry. We have also shown that the establishment of these asymmetries follows the same temporal order as in the embryo and uses similar molecular mechanisms. These observations have created an excellent experimental system to study early embryonic events ex vivo. Specifically we have shown that it is an excellent system to understand the relationship between decisions at the level of single cells and in large, spatially constrained, populations. Our work so far has focus on two aspects: the symmetry breaking events and the generation, in our gastruloid system, of a special stem cell population which drives the generation of the spinal cord and the thoracic muscles and ribs and have begun to shed some light in the molecular events governing these processes.