MULTISCALE PHYSICS OF MORPHOGENESIS
Principal investigator: Hervé TurlierLaboratory website
Invaluable progress has been made last decades in the molecular, genetic and cellular characterization of morphogenetic processes. Yet, the precise physical processes governing the shape and dynamics of cells remain poorly characterized. The laboratory is developing theoretical models of morphogenesis, combining physics, mechanics and advanced numerical simulations. To understand how morphology controls biological functions, and, ultimately, how multicellular systems self-organize, we aim at integrating molecular, cellular and multicellular levels of description (see Fig. 1) into a new and versatile simulation framework for embryo morphogenesis: Virtual Embryo.
From Molecular to Mesoscopic Models of the Actomyosin Cortex
As elegantly illustrated by D’Arcy Thompson back in 1917, cells in suspension or in tissues adopt spatial configurations remarkably similar to soap bubbles, an analogy which can be drawn from the physical concept of surface tension. In animal cells, the surface tension is mainly provided by the contractile forces generated by molecular motors within the actin-myosin (or actomyosin) cortex, a thin layer of polymeric filaments, which lies under the plasma membrane. In contrast to passive objects like bubbles, cortical tension is actively regulated in space & time by several biochemical pathways –such as the RhoA signaling cascade - and strongly depends on the deformations of the layer. From a biological perspective, the tools available to perturb the cortex operate at the molecular level (chemical drugs, genetic engineering and environmental cues). Characterizing quantitatively how the self-organization and regulation of molecular players in the cortex (actin filaments, myosin motors, crosslinkers etc...) control its coarse-grained physical properties (elasticity, fluidity, contractility etc...) represents therefore a critical step to directly relate experiments to quantitative models. At the cellular scale, the recent active-gel hydrodynamic theories have proven their efficiency in capturing the essential physics of various actomyosin based dynamical cell processes. However their relation to microscopic properties of actomyosin networks remains unclear, and no generic tool is available to simulate the mechanics of active surfaces in 3 dimensions. Combining physical modeling and numerical simulations, we aim at filling these gaps in collaboration with experimental groups.
From Cellular to Multicellular Models of Morphogenesis
At the multicellular level, morphogenesis is furthermore regulated by mechanical interaction & biochemical communication between cells, and by external mechanical constraints. In particular, the interplay between cell contractility, cell-cell adhesion, molecular expression and fate specification remains poorly understood in early embryos and small tissues. To identify and understand the minimal self-organization principles driving multicellular morphogenetic processes, it is essential to develop realistic 4D models of interacting cells, offering general & accurate description of cell surface mechanics but also complemented by versatile options to model surface signaling dynamics and simple gene networks regulation.
The morphogenesis of early embryos is the main biological focus and guideline for developing new theoretical tools in the laboratory. Our research is supported, on the experimental side, by a close collaboration with the laboratory of Dr. Jean-Léon Maître in Institut Curie, working on the mechanics of early mammalian embryos. In mammalian species, early embryos develop over several days, which leads to a decoupling between morphogenetic timescales (several hours) & typical viscous relaxation timescales (a few minutes). Dynamics is limited in this case first by the slow regulation of surface tensions, and morphogenesis is well captured by a quasi-static mechanical description, as we recently proposed for compaction and for the formation of the inner-cell mass in the mouse embryo (Maître, Turlier et al. 2016). At the opposite, most non-mammalian embryo types, such as marine animals or insects, develop on much shorter timescales, of the order of a few hours. In this case, viscous dissipation becomes essential to consider again as it constitutes a main factor limiting cell shape dynamics (Turlier et al. 2014). On such timescales, the biophysical characterization and precise modeling of cell divisions and its mechanical coupling to the rest of the embryo is an essential point, that we aim particularly to integrate into realistic simulations of embryo morphogenesis.
Figure 1. Schematic illustration of the multiple spatiotemporal scales implicated in the morphogenesis of early embryos or small tissues. Note that there is no causal hierarchy between scales: larger scales can feedback on lower scales, reflecting the importance of a multiscale and integrated approach of morphogenesis.
Figure 2. Numerical simulations of the process of cytokinesis in cell division, where the actomyosin cortex is described as a thin layer of viscous active gel (from Turlier et al. 2014).
Figure 3. Numerical simulations of compaction and cell internalization processes in the early mouse embryo. (from Maître, Turlier et al. 2016).
Maître, J.-L., Niwayama, R., Turlier, H., Nédélec, F., and Hiiragi, T. (2017). Corrigendum: Pulsatile cell-autonomous contractility drives compaction in the mouse embryo. Nat. Cell Biol. 19, 1003.
Turlier, H., Fedosov, D.A., Audoly, B., Auth, T., Gov, N.S., Sykes, C., Joanny, J.-F., Gompper, G., and Betz, T. (2016). Equilibrium physics breakdown reveals the active nature of red blood cell flickering. Nat Phys 12, 513–519.
Maître, J.-L., Turlier, H., Illukkumbura, R., Eismann, B., Niwayama, R., Nédélec, F., and Hiiragi, T. (2016). Asymmetric division of contractile domains couples cell positioning and fate specification. Nature 536, 344–348.
Turlier, H., and Maître, J.-L. (2015). Mechanics of tissue compaction. Semin. Cell Dev. Biol. 47–48, 110–117.
Maître, J.-L., Niwayama, R., Turlier, H., Nédélec, F., and Hiiragi, T. (2015). Pulsatile cell-autonomous contractility drives compaction in the mouse embryo. Nat. Cell Biol. 17, 849–855.
Turlier, H., Audoly, B., Prost, J., and Joanny, J.-F. (2014). Furrow constriction in animal cell cytokinesis. Biophys. J. 106, 114–123.
Bun, P., Liu, J., Turlier, H., Liu, Z., Uriot, K., Joanny, J.-F., and Coppey-Moisan, M. (2014). Mechanical checkpoint for persistent cell polarization in adhesion-naive fibroblasts. Biophys. J. 107, 324–335.