How do forces shape life?
|In living systems, molecules can self-organize into large functional assemblies. We are an interdisciplinary lab trying to discover the biophysical principles behind this self-organization. A particular focus of our research regards how active forces shape biological structures such as mitotic spindles, microtubule asters, and chromatin. We combine concepts and tools across cell biology, biochemistry, and soft matter physics.|
How forces shape the cytoplasm
|During embryonic development, cells rapidly divide and reorganise their content on millimetre scales. For example, throughout the cell cycle, the microtubule and actin cytoskeleton undergo dramatic changes, generating distinct physical environments in the cell. We explore this dynamic organisation by using cytoplasmic extract from X. laevis frog eggs and D. rerio zebrafish embryos as model systems. We employ microscopy, rheology, laser cutting, quantitative image analysis and theory. Altogether, this allows us to identify simple physical mechanisms that govern the organisation of the cytoplasm during the cell cycle and bridge the gap from molecular level to macroscopic organisation.|
How forces shape the nucleus
|Confining the long DNA molecule within the nucleus in a functional way requires organization across different scales. By combining polymer physics with single-molecule imaging, we have characterized two different types of forces that act on DNA: Pioneering transcription factors, that condense DNA through capillary forces, and motor proteins, that extrude DNA loops. By using a reconstituted nucleus in X. laevis extract, we are currently dissecting how these molecular forces scale up and can lead to the micron-scale organization of chromatin.|
Recent research highlights
What are the molecular and physical principles that govern the emergence of tissue topology during morphogenesis? By studying the self-organisation of neuroepithelial organoids, we discovered that tissue topology emerges from two topologically distinct modes of epithelial fusion: trans-fusion, in which two separate epithelia fuse, and cis fusion, in which the self-fusion of a single epithelium creates a loop.
K. Ishihara, A. Mukherjee, E. Gromberg, et al., Nat. Phys. 2022
How are active flows generated in spindles? Combining experiments and large-scale numerical simulations, we show that a gelation transition enables long-range microtubule transport causing the spindles to self-organize into two oppositely polarized microtubule gels. This work uncovers the connection between spindle rheology and architecture in spindle self-organization.
Dalton, B.A., Oriola, D., Decker, F, and Brugués J. A gelation transition enables the self-organization of bipolar metaphase spindles. Nat. Phys. 2022
How is transcriptional machinery brought together in space and time? We discovered that protein condensates perform work and generate capillary-like forces that pull DNA together. These forces pull DNA into transcription factor condensates in a mechanosensitive manner. These findings provide a novel physical mechanism that the cell nucleus could use to organize the genome in general or in particular for potentially underpinning how enhancer-promoter contacts are coordinated in transcription.
Quail, T., Golfier, S., Elsner, M. et al. Force generation by protein–DNA co-condensation. Nat. Phys. 2021
How do mitotic spindles scale with cell size? We used quantitative microscopy in living zebrafish embryos and Xenopus egg extracts in combination with theory to show that microtubule polymerization dynamics are insufficient to scale spindles and only contribute below a critical cell size. In contrast, microtubule nucleation governs spindle scaling for all cell sizes. We show that this hierarchical regulation arises from the partitioning of a nucleation inhibitor to the cell membrane.
Rieckhoff E., Berndt F., Elsner M., et al., Spindle Scaling Is Governed by Cell Boundary Regulation of Microtubule Nucleation, Current Biology, 30 (24), 4973-4983, (2020)
How do mitotic spindles grow? We developed an assay based on laser ablation to directly probe microtubule nucleation events in Xenopus laevis egg extracts. Combining this method with theory and quantitative microscopy, we showed that the size of a spindle is controlled by autocatalytic growth of microtubules, driven by microtubule-stimulated microtubule nucleation. The autocatalytic activity of this nucleation system is spatially regulated by the limiting amounts of active microtubule nucleators and provides an upper limit to spindle size.
Decker F., Oriola D., Dalton B., and Brugués J., Autocatalytic microtubule nucleation determines the size and mass of Xenopus laevis egg extract spindles, eLife 7:e31149, 2018.