Session L7: System Biology I: The Physics of Development

Robustness in multicellular systems

Cells and organisms cope with the task of maintaining their phenotypes in the face of numerous challenges. Much attention has recently been paid to questions of how cells control molecular processes to ensure robustness. However, many biological functions are multicellular and depend on interactions, both physical and chemical, between cells. We use a combination of mathematical modeling and molecular biology experiments to investigate the features that convey robustness to multicellular systems. Cell populations must react to external perturbations by sensing environmental cues and acting coordinately in response. At the same time, they face a major challenge: the emergence of conflict from within. Multicellular traits are prone to cells with exploitative phenotypes that do not contribute to shared resources yet benefit from them. This is true in populations of single-cell organisms that have social lifestyles, where conflict can lead to the emergence of social ``cheaters,'' as well as in multicellular organisms, where conflict can lead to the evolution of cancer. I will describe features that diverse multicellular systems can have to eliminate potential conflicts as well as external perturbations.   

Axis Specification in Hydra

Hydra is an about cm sized polyp of roughly 10$^5$ cells exhibiting surprising robustness: it can regenerate even from a random cell aggregate made from its own cells. During such a reorganization, hydra first forms a hollow cell sphere. We show that even a weak temperature gradient directs the axis of the regenerating animal -- but only if it is applied during the symmetry-breaking moment. We observe that the spatial distribution across the cell sphere of the early expressed, head-specific gene ks1 has become scale-free and fractal at that point. We suggest that in order to break the symmetry and define an axis during the regeneration process, the cell network organizes towards a state, that is characterized by an unusually high sensitivity to external perturbation as well as spatially self-similar gene expression patterns. The observed behavior arises naturally from next-neighbor cell communication, when long-range signaling as required for axis definition is achieved through increased synchronization of expression profiles. Numerical results in progress show that our observations can be robustly reproduced with avalanches of gene expression patterns generated from gene switching above a stimulation threshold.   

Surface cell differentiation controls tissue surface tension and tissue positioning during zebrafish gastrulation

Differences in tissue surface tension (TST) between different tissue types are thought to guide tissue organization and cell sorting in development. Measurements of TST have been useful to predict the outcome of in vitro cell sorting and envelopment experiments. However, the outcome of cell sorting experiments in vitro often substantially differs from tissue positioning in vivo, raising questions as to the actual contribution of TST to tissue positioning within the developing embryo. Here, we show that surface tension of germ layer tissues during zebrafish gastrulation critically relies on the differentiation of their surface cells. We also show that surface differentiation of the different germ layer tissues varies and is considerably different between the situation in vitro and in vivo, explaining the apparent dissimilar outcome of cell segregation between these two situations. To analyze germ layer TST as a function of surface cell differentiation, we interfere with surface cell properties of germ layer aggregates by misexpressing genes involved in surface cell differentiation specifically within surface cells using the GAL4-UAS system, and measure tissue surface tension using both parallel plate compression and micropipette aspiration techniques. Our data provides evidence in favor of a critical function of surface cell differentiation in modulating TST and subsequently tissue positioning within the developing embryo.   

Self-organized cytoskeletal dynamics during fruit fly epithelial morphogenesis

Epithelial morphogenesis plays a major role in embryonic development. During this process cells within epithelial sheets undergo complex spatial reorganization to form organs with specific shapes and functions. The dynamics of epithelial cell reorganization is driven by forces generated through the cytoskeleton, an active network of protein filaments and motor proteins. In this talk, I will present a novel mesoscopic-scale physical description of force generation by the cytoskeleton, and show that this minimal description can account for a wide range of phenomena associated with fruit fly epithelial morphogenesis.   

Collective Chemotactic Cell Movement; a Key Mechanism of Development and Morphogenesis

We investigate the molecular mechanisms by which cells produce and detect chemotactic signals and translate this information in directed movement up or down chemical gradients in the social amoebae \textit{Dictyostelium discoideum,} and during gastrulation in the chick embryo. Investigation of Dictyostelium mutants with changes in cAMP cell-cell signalling dynamics and chemotaxis, show how cellular heterogeneity in signalling dynamics and polarised activation of the actin-myosin cytoskeleton drive aggregation, cell sorting, slug formation and migration. Chemotactic cell movement also plays a critical role during gastrulation in the chick embryo a model for amniote development. We suggest that epiblast cell movement during the formation of the primitive streak as well as the movement of the mesoderm cells after their ingression through the streak is controlled by a combination of attractive and repulsive guidance cues. We use computer models explore signalling and cell movement interact to give rise to emergent phenomena at the tissue and organism level such as pattern formation and morphogenesis.