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Physical and Molecular Principles Governing Cytoskeletal Organization

Our goal is to understand how cytoskeletal proteins cooperate for cells to exert forces or resist mechanical stress.

The cellular cytoskeleton is composed of proteins that can polymerize in the form of tubes or filaments. These biological polymers form a dense and organized meshwork that allows cells to resist mechanical constraints, or to exert forces through the action of molecular motors or from the reorganization of these networks. The cytoskeleton is essential for many cellular functions such as migration or division.

All known living organisms have a cytoskeleton, and some polymers such as actin and microtubules are extremely conserved in eukaryotes. In mammals, many diseases and in particular certain types of cancers are related to defects of the cytoskeleton. Thus, understanding from a fundamental point of view all the subtleties of its functioning is essential to explain certain pathological cellular behaviors.

The main objective of the team is therefore to understand how the polymers of the cytoskeleton and their multiple associated regulatory proteins function together in the cell. To solve this problem, we mainly adopt a reductionist approach based on the idea that any biological process is well understood from the moment when we are able to reconstitute it from its most elementary building blocks. Our work therefore consists first of identifying key molecules through genetic and cell biology approaches. Then, the purification and biochemical analysis of these compounds allows us to predict their functions within complex molecular interaction networks. Finally, we develop a variety of biomimetic systems to reproduce and analyze the behaviors observed in the cell. This work requires a strong interdisciplinarity, at the crossroads of biology, chemistry and physics.

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“The actin and the balloon”: Branched actin-based motility assay

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Audrey Guillotin
CNRS Engineer, Grenoble
Micaela Boiero Sanders
Post-doc, Max Planck Institute, Dortmund
Adrien Antkowiak
Post-doc, University of Grenoble
Jessica Colombo
Consultant at Korner Klanik
Reda Belbahri
Engineer at Akka Technologies
Christopher Toret
Post-doc, the University of Geneva
Thomas Le Goff
Post-doc

Funding bodies

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CENTURI
Fondation Recherche Medicale

Gallery

Yeast actin cytoskeleton visualized by phalloidin staining, by Micaela Boiero Sanders.
“The actin fireballs”: Actin assembly from formin-coated beads, by Adrien Antkowiak.

Physical and Molecular Principles Governing Cytoskeletal Organization

Mechanics of cell contacts and their remodelling

During tissue formation, cell contacts are remodelled by changes in adhesion forces and cell contractility (Lecuit and Lenne, Nature Rev Mol Cell Bio, 2007). To identify the nature of these forces and the mechanical properties of the contacts, we develop and apply physical methods such as laser nanodissection and optical tweezers micromanipulation (Bambardekar et al, PNAS 2015), which are now becoming widespread in the community. Quantification of cell shape changes induced by laser micromanipulation provides direct measurements of the forces acting at cell contacts, and reveals the viscoelastic properties of the tissue (Clément et al, Current Bio 2017). We have shown, using these methods, the distribution of forces (dependent on the molecular motor Myosin-II) that remodel cell contacts during epithelial morphogenesis (Rauzi, Nature Cell Bio 2008). We have shown the importance of geometry in the application of forces shaping cell contacts (Kale et al, Nature Comm 2018). We have highlighted the central role of viscous dissipation in cell and tissue shape changes (Clément et al, Current Bio 2017). The methods developed in our team, coupled with genetic perturbation and mechanical modeling, also reveal how adhesion molecules quantitatively control cell shapes by coupling to contractile forces (Chan, Shivakumar, eLife 2017).
With these approaches, we continue exploring several aspects of cell contact mechanics including the dynamic interplay of adhesion, biochemical signaling, and actomyosin contractility shapes cell contacts using Drosophila and C. elegans embryos as model systems.

Mechanochemical state changes in multicellular self-organization

The formation of multicellular organisms is based on symmetry breaking and tissue patterning events. Among these, the process of gastrulation transforms an apparently homogeneous group of cells into the outline of an organism with recognisable body axes and tissue layers. Our aim is to understand the organizational principles underlying the process of gastrulation in mammals, using an in vitro system composed of embryonic stem cells, called gastruloid. We have recently shown how differentiation, coupled with a change in the mechanical behavior of cells, generates large-scale flow, which in turn polarizes the multicellular system and defines distinct germ layers (Hashmi et al, eLife 2022). This mechanism is reminiscent of the process that occurs at the primitive streak in the embryo and has the characteristics of a mechanochemical phase transition (Lenne and Trivedi, Nature Comm 2022).

New approaches to tissue morphogenesis

Our team has developed and applied over the years several approaches to study cell dynamics and tissue morphogenesis. Such approaches include mechanical measurements and imaging methods. To probe the mechanics of cells in tissues, we introduced optical tweezers for direct manipulation of cell contacts (Bambardekar, PNAS 2015; Chardès et al, JOVE 2018). We have validated and implemented force inference methods in epithelia from cell and tissue scale (Kong et al, 2019, Code available here). We strive to implement long-term imaging methods, including light sheet and non-linear microscopy,  to image the multicellular choreography and the changes of biochemical states leading to the formation of tissues and organs.