Periodic Reporting for period 4 - MECHABLASTO (Morphogenesis during pre-implantation development: molecular and mechanical regulation)
Período documentado: 2022-08-01 hasta 2023-01-31
During the first days of its life, the mammalian embryo forms a structure called the blastocyst, which is responsible for implanting the embryo within its mother. The architecture of the blastocyst is established through a fascinating choreography of cell movements and deformation, which determines which cells will be part of the embryo and of the placenta. Eventually, a fluid-filled pocket forms between the cells of the blastocyst, which will determine the site of implantation and the future dorso-ventral axis of the animal. Our research aims at understanding what controls the establishment of the architecture of the blastocyst. For this, we study the forces controlling the shape changes and we identify the genes controlling those forces.
During the project, we have identified how the fluid infiltrating the mammalian embryo determines the position its dorso-ventral axis. We filmed the formation of the fluid-filled pockets under a microscope at unprecedented resolution. Surprisingly, the fluid, under high pressure, breaks through the contacts between cells in a process of hydraulic fracturing, or fracking, similarly to the method used to extract gas from bedrocks. This results in many small water pockets far apart stuck in between cells. Together into a single entity, these water pockets do not coalesce but rather exchange fluid in a process akin to Ostwald ripening, similarly to the demixing of oil and vinegar in a vinaigrette. Thanks to this novel conceptual framework, we could design new experiments and we became the first to succeed in manipulating the position of the fluid-filled pocket and of the dorso-ventral axis of the mouse embryo (Dumortier et la, 2019 Science).
This work reveals the fascinating changes in material properties of the early mammalian embryo and the unexpectedly exotic ways embryos have found to shape themselves. The mechanisms of hydraulic fracturing has since been reported in two other in vivo contexts and been modeled using in vitro reconstitution. This first publication of the lab quickly led to another striking discovery: protrusions growing inward at cell-cell contacts due to the local confinement provided by adhesion molecules. We have characterised the formation of these protrusions and propose that cells use them to redistribute the intercellular fluid (Schliffka et al, 2023 bioRxiv). In addition, we have discovered that to accumulate into the embryo, the fluid travels to a large extent through the cells (Schliffka, Tortorelli et al, 2021 eLife).
On the longer term, such gained knowledge will help better understanding our own embryonic development during a phase that is critical and causes frequent miscarriages. Therefore, we hope this will contribute to the global effort to improve the fertility of the ageing European population.
To help further with this, we have screened for genes involved in morphogenesis using zygotic CRISPR knockout and found that cell fragmentation, a deleterious process often observed in human embryos, occurs during mitosis as a result of aberrant signals that we have characterised (Pelzer et al, 2022 bioRxiv). This deleterious process is also favoured by cells contractile activity, which we discovered is heavily reorganized during the first two days of mouse development (Özgüç et al, 2022 PLOS Biology).
This work reveals the fascinating changes in material properties of the early mammalian embryo and the unexpectedly exotic ways embryos have found to shape themselves. The mechanisms of hydraulic fracturing has since been reported in two other in vivo contexts and been modeled using in vitro reconstitution. This first publication of the lab quickly led to another striking discovery: protrusions growing inward at cell-cell contacts due to the local confinement provided by adhesion molecules. We have characterised the formation of these protrusions and propose that cells use them to redistribute the intercellular fluid (Schliffka et al, 2023 bioRxiv). In addition, we have discovered that to accumulate into the embryo, the fluid travels to a large extent through the cells (Schliffka, Tortorelli et al, 2021 eLife).
On the longer term, such gained knowledge will help better understanding our own embryonic development during a phase that is critical and causes frequent miscarriages. Therefore, we hope this will contribute to the global effort to improve the fertility of the ageing European population.
To help further with this, we have screened for genes involved in morphogenesis using zygotic CRISPR knockout and found that cell fragmentation, a deleterious process often observed in human embryos, occurs during mitosis as a result of aberrant signals that we have characterised (Pelzer et al, 2022 bioRxiv). This deleterious process is also favoured by cells contractile activity, which we discovered is heavily reorganized during the first two days of mouse development (Özgüç et al, 2022 PLOS Biology).
This work reveals the fascinating changes in material properties of the early mammalian embryo and the unexpectedly exotic ways embryos have found to shape themselves. In particular, it showed that the first axis of symmetry of the mammalian embryo is set by the physical properties of the embryo. Future research will be needed to explore additional physical properties and to test the validity of these findings in other mammalian species, including humans.