Collaborative Research: A Mechanical Atlas for Embryogenesis at Single-Cell Resolution

The intricate 3D structures of multicellular organisms emerge through genetically encoded spatiotemporal patterns of mechanical stress. Cell atlases of gene expression during embryogenesis are now available, but connecting gene expression to mechanical design principles that govern the emergence of embryo shape demands an ability to measure mechanical stresses at single-cell resolution, across embryos, over time. The main objectives of this work are to construct a single-cell mechanical atlas, in 3D and in physical units, during the process of gastrulation in the ascidian embryo. To do so, we will solve an inverse problem, grounded in a new physical theory of multicellular aggregates, advanced light-sheet based imaging, and biophysical measurements of material parameters. We will use this mechanical atlas as a foundation to explore how dynamic control of force generation by actomyosin, and dynamic coupling between neighboring cells, encodes robust stereotyped morphogenetic trajectories. The intellectual merits of the proposed work are: Surprisingly, our mapping out of Cell Atlases based on single-cell RNA sequencing far outpaces our ability to construct Mechanical Atlases for developing organisms. As such, a mechanical atlas would allow biologists to more completely and quantitatively investigate the nature of the genotype-to-phenotype map in complex multicellular organisms and physicists to study the emergent mechanical properties manifest at the multicellular scales of development. The two atlases are not independent, thus in the long run the work proposed here will help the community in studying the interplay between them. Even more broadly, the two research objectives combined give case studies and general purpose tools that will reformulate the dominant paradigm of how development occurs, placing the patterning of physical and chemical form on an equal footing wherein the two are intricately coupled to produce robust self organization in multicellular life forms. Broader impacts of the proposed work are: In the long run this research objective has the potential to contribute to the fields of tissue engineering, organoid biology, and stem cell therapies, which are aimed at engineering theraputic solutions. In order to chart a course through engineering design space requires having atlases. And for now, we only have access to one aspect of the Atlas, and are lacking how the dynamics of fate-specification rely on, and give rise to, complex three dimensionally shaped tissues and organs. One arena in which this interplay between chemical and physical form plays out as a beautiful orchestra is the embryo, hence constructing and understanding these two atlases must be first done in the embryo so as to uncover the principles that govern how pattern formation can occur, and be controlled, in multicellular systems.