Stem-cell derived in vitro systems, such as organoids or embryoids, hold great potential for modeling in vivo development. Full control over their initial composition, scalability, and easily measurable dynamics make those systems useful for studying specific developmental processes in isolation. Here we report the formation of gastruloids consisting of mouse embryonic stem cells (mESCs) and extraembryonic endoderm (XEN) cells. These XEN-enhanced gastruloids (XEGs) exhibit the formation of neural epithelia, which are absent in gastruloids derived from mESCs only. By single-cell RNA-seq, imaging, and differentiation experiments, we demonstrate the neural characteristics of the epithelial tissue. We further show that the mESCs induce the differentiation of the XEN cells to a visceral endoderm-like state. Finally, we demonstrate that local inhibition of WNT signaling and production of a basement membrane by the XEN cells underlie the formation of the neuroepithelial tissue. In summary, we establish XEGs to explore heterotypic cellular interactions and their developmental consequences in vitro.

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Embryogenesis is a fascinating mystery. How a single fertilized egg, the zygote, reads out its genetic information and turns into a fully formed, multicellular organism still defies detailed understanding. An adult organism can consist of trillions of cells of different types, organized to form various complex tissues and organs. To obtain such a system starting from a single cell requires an incredibly sophisticated combination of three key processes: cell division, differentiation and migration. Cell division turns a parent cell into two genetically identical copies, the daughter cells. Differentiation is the process by which a cell transforms into a particular cell type with a highly specialized function, such as a neuron, a bone cell or a muscle cell. While cells of different types have identical genomes, they express distinct sets of proteins that define the cells’ function and shape. Finally, directed cell migration is crucial to obtain proper three-dimensional organization and thereby correctly formed tissues and organs. Over many decades, several model organisms have been used to study the development of insects (Drosophila), fish (Zebrafish), amphibians (Xenopus), avians (Chicken), and mammals (Mouse, Human). In this thesis, we present three studies of different stages of mammalian embryogenesis...@en