Segmentation in mouse gastruloids
A few years ago the Martinez Arias group, reported a model system to study mammalian development. Using mouse embryonic stem cells, they found that under defined culture conditions, precise numbers of cells would aggregate and undergo a series of events that mimic the early embryos. In particular, they broke symmetry, segregated germ layers and produced the blueprint of a mammal in the form of a genetic body plan. This model system opened represents an advance for developmental biology as it complements studies with mouse embryos and provides insights that could not be reached otherwise. An intriguing observation from the early studies was a disconnect between the organization of gene expression in gastruloids, very similar though not identical to that of the embryo, and a total lack of cellular organization. For example, the spinal cord is a group of neurons organized in space with regard to a coordinate system that arranges them precisely along a dorsoventral axis. In the gastruloids, the neurons are there but disorganized. Another example is the process of somitogenesis that gives rise to the progenitors of ribs, vertebrae and thoracic muscles in the form of blocks of epithelial tissues, called somites. The process is associated with a conveyor belt of gene expression from the tail, through a block of undifferentiated mesoderm, to the epithelial block or somites. In the gastruloids, the belt of gene expression is there but the cells are similar independently of what genes they express.
In a new publication, in collaboration with the group of Alexander van Oudenaarden at the Hubrecht Institute in Utrecht (The Netherlands), the Martinez-Arias/Moris group perform a single cell analysis of gastruloids after 5 days in culture and show a degree of complexity of cellular types that matches the embryo with the already known exception of a brain. In this survey they expand on the gene expression signature associated with somitogenesis and show how similar it is, in space, to that of the embryo. Furthermore, they notice a dynamic of gene expression in the form of oscillations that mirrors the embryo. Most significantly, they show that embedding gastruloids in Matrigel (a complex mixture of extracellular matrix components) is able to trigger the formation of somites within the domain of gene expression that corresponds to somites. This is a surprising observation that reveals how the mechanics of tissues influences the developmental programs and opens up possibilities to tackle it experimentally.
References
Beccari, L., Moris, N., Girgin, M., Turner, D., Baillie-Johnson, P., Cossy, A.C., Lutolf, M., Duboule, D. and Martinez Arias, A. (2018) Multiaxial self organization properties of mouse embryonic stem cells gastruloids. Nature 562, 272-276.
Turner, DT., Hayward, P., Baillie Johnson, P., Broome, R., Rue, P., Faunes, F. and Martinez Arias, A. (2014) Wnt/ß-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse ES cells. Development 141, 4242-4253.
Turner DA, Girgin M, Alonso-Crisostomo L, Trivedi V, Baillie-Johnson P3, Glodowski CR, Hayward PC, Collignon J, Gustavsen C, Serup P, Steventon B, P Lutolf M, Martinez Arias A. (2017) Anteroposterior polarity and elongation in the absence of extra-embryonic tissues and of spatially localised signalling in gastruloids: mammalian embryonic organoids. Development 144, 3894-3906.
van den Brink, S., Baillie-Johnson, P., Balayo, T., Hadjantonakis, AK., Nowotschin, S., Turner, DA. And & Martinez Arias, A. (2014) Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse ES cells. Development 141, 4231-4242.
van den Brink,S., Alemany,A., van Batenburg,V. Moris, N., Anlas, K., Blotenburg, M., Turner, D., Vivié, J., Martinez Arias, A. and Oudenaarden, A. (2020) Single cell and spatial transcriptomics reveals somitogenesis in gastruloids. Nature (2020) https://www.nature.com/articles/s41586-020-2024-3