Impact of tissue morphology on pluripotent stem cell identity and fate

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Mammals develop from a small group of pluripotent stem cells that have the task to generate all the cell types and tissue shapes ofthe organism in an organised manner. How they achieve this is an important and unsolved problem in biology. Most studies ofmammalian development have focused on identifying changes in gene expression that guide tissue morphogenesis. However, recentevidence indicates that changes in tissue shape impinge on gene regulatory networks to affect cell fate. This additional yet elusivelayer of fate control allows cells to adapt to their dynamic environment. The link between tissue shape and cell fate is particularlyrelevant at implantation, when the embryo undergoes a dramatic reorganisation as it comes into physical contact with the uterus.This is a critical period in mammalian development associated with changes in gene expression, cell organisation, and overall embryopatterning and morphology, but is poorly understood due to the inaccessibility of the embryo. To overcome this limitation, werecently established embryo culture methods and 3D stem cell models that faithfully recapitulate development at implantation. Weaim to dissect how changes in cell identity, cell organisation, and tissue shape are coordinated in mouse and human embryos toensure the formation of the body plan. Employing state-of-the-art transcriptomics, proteomics, imaging and functional in vivoexperiments, we will determine how the organisation of pluripotent stem cells into an epithelial tissue at implantation affects theiridentity and subsequent specification into distinct cell types. Capitalising on our unique embryo and stem cell cultures thatrecapitulate the shape-fate crosstalk at implantation, this project is uniquely well-poised to yield an integrated mechanisticunderstanding of normal embryo development, a first fundamental step in identifying the causes of developmental failure,congenital abnormalities and infertility.