Physics of the first mammalian epithelium

ongoing

Epithelia operate major biological functions throughout the human body. Forming de novo during preimplantation development, the trophectoderm (TE) is our first epithelium. The TE mediates the formation of the first mammalian lumen, which involves considerable physical challenges. Indeed, pressurized fluid, pumped through the TE, fractures intercellular contacts before cells squeeze this fluid into a single lumen. We recently found that cell adhesion and cell contractility determine the position of this lumen, which then controls further differentiation of the TE. This suggests that physical cues can determine the first mammalian axis of symmetry and TE patterning. However, most physical properties of epithelia controlling this process remain unknown, as their study in vivo has been so far very limited. In this project, we will investigate how the physics of the TE shapes and patterns the mouse preimplantation embryo, by using novel approaches, such as microfluidics and optical tweezers, that allow direct measurement of physical properties in vivo. First, we will determine epithelial transport properties of the TE and their regulation during lumen opening. We will next map plasma membrane reservoirs and membrane mechanics during preimplantation development. We will then characterize how the nuclear envelope and chromatin regulate nuclear mechanics during epithelial thinning. With this broad and unprecedented in vivo physical characterization, we will determine how epithelial transport, plasma membrane and nuclear mechanics influence epithelial stretching and patterning during lumen growth and positioning. Finally, we will determine the relative contributions of these physical properties in this process, and investigate their relationship. Together, we will build an integrated view of how uncharted physical properties of epithelia control stretching and patterning, in the context of a process that is key to the fertility of the ageing European population.