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Spatio-temporal and mechanical control of motile structures

Project Summary

Cells have the ability to adjust their adhesive and cytoskeletal organizations according to changes in the biochemical and physical nature of their surroundings. In return, by adhering and generating forces on neighboring cells and extracellular matrices cells control their environment, shape and movement. This is true from integrin-based adhesive structures of migrating cells to synapses of neurons. Those adhesive structures are the converging zones integrating biochemical and biomechanical signals arising from the extracellular space and the actin cytoskeleton. Thus, the life-cycle of adhesive and cytoskeletal structures are involved in critical cellular functions such as migration, proliferation and differentiation, and regulate cell behavior in many physiological responses such as development. Alterations of adhesive and cytoskeletal organizations contribute to pathologies including cancer, but also cognitive disorders.

At the molecular, sub-cellular, and cellular levels, cell shaping and motility proceed through cycles lasting from seconds to minutes. During those cycles, critical proteins undergo stochastic motions and transient interactions that are essential to their functions. Regulation of these interactions by forces is at the base of mechano-transduction events controlling cell behavior. Therefore, to understand the molecular mechanisms controlling the life cycle of motile structures, it is crucial to study the position and dynamics of proteins but also their interactions and how mechanical forces control these molecular events.

Our goal is to decipher at the molecular level the spatiotemporal and mechanical mechanisms which control the architecture and dynamics of motile structures including integrin-based AS, the lamellipodium and dendritic spines. Exploration of these new dimensions requires an innovative and multidisciplinary approach combining cell biology, biophysics, biomechanics and advanced optical microscopy techniques including super-resolution microscopy, single protein tracking and quantitative image analysis.

We are developing three specific axes:
1/ Integrin adhesion
2/ Actin in dendritic spines
3/ Super-resolution developments

Keys Publications

Integrins β1 and β3 exhibit distinct dynamic nanoscale organizations inside focal adhesions.
Rossier O, Octeau V, Sibarita J-B, Leduc C, Tessier B, Nair D, Gatterdam V, Destaing O, Albigès-Rizo C, Tampé R, Cognet L, Choquet D, Lounis B, Giannone G.
Nature Cell Biology. 2012. 14,1057-67.

Nanoscale segregation of branched F-actin nucleation and elongation factors determines dendritic spine protrusions.
Chazeau A., Mehidi A., Nair D., Gautier J., Leduc C., Chamma I., Kage F., Kechkar A., Thoumine O., Rottner K., Choquet D., Gautreau A., Sibarita J.B., Giannone G. (2014) EMBO J. 2014. 33, 2745-2764.

The cancer cell glycocalyx mechanically primes integrin-dependent growth and survival.
Paszek MJ, Dufort CC, Rossier O, Bainer R, Mouw JK, Godula K, Hudak JE, Lakins JN, Wijekoon AC, Cassereau L, Rubashkin MG, Magbanua MJ, Thorn KS, Davidson MW, Rugo HS, Park JW, Hammer DA, Giannone G, Bertozzi CR, Weaver VM.
Nature. 2014. 511, 319–325.

Neurexin-1β binding to neuroligin-1 triggers the preferential recruitment of PSD-95 versus gephyrin through tyrosine phosphorylation of neuroligin-1.
Giannone G*, Mondin M*, Grillo-Bosch D, Tessier B, Saint-Michel E, Czöndör K, Sainlos M, Choquet D, Thoumine O.
Cell Reports. 2013. 27, 3(6), 1996-2007.

Dynamic super-resolution imaging of endogenous proteins on living cells at ultra-high density.
Giannone, G., Hosy, E., Levet, F., Constals, A., Schulze, K., Sobolevsky, A. I., Rosconi, M. P., Gouaux, E., Tampé, R., Choquet, D. and Cognet, L.
Biophys J. 2010. 99, 1303-1310.

Lamellipodial Actin Mechanically Links Myosin Activity with Adhesion-Site Formation.
Giannone, G., Dubin-Thaler, B. J., Rossier, O., Cai, Y., Chaga, O., Jiang, G., Beaver, W., Dobereiner, H. G., Freund, Y., Borisy, G., and Sheetz, M. P.
Cell. 2007. 128, 561-575.

Team leader: Grégory Giannone

Contact: Grégory Giannone, tel. +33 (0)5 33 51 47 08

Grégory Giannone explores the spatiotemporal and mechanical mechanisms driving the dynamics of structures and proteins regulating cell motility

Cell motility and shape are controlled by biochemical and biomechanical signals which induce the local assembly or disassembly of adhesives and protrusive structures. During his PhD (1997-2001) in Kenneth Takeda laboratory (Louis Pasteur University, France), Grégory Giannone studied the correlation between intracellular calcium oscillations and integrin-dependent adhesion site disassembly. During his post-doc (2001-2005) in Michael Sheetz laboratory (Columbia University, New York), he used high resolution microscopy, optical tweezers and quantitative analysis to study the temporal and spatial dynamics of structures involved in cell motility. He has elucidated the periodic nature of cell edge extension and adhesion site initiation. He also demonstrated the fundamental role of mechanical coupling between the actin cytoskeleton and integrins during cell migration.

Grégory Giannone started as a CNRS researcher in 2005 in the group of Daniel Choquet. To step towards higher spatial and temporal resolution, from the micron-scale coordination of sub-cellular structures to the nanometer-scale coordination of proteins, he developed projects based on super-resolution imaging and innovative single protein tracking methods. He created a new method of super-resolution imaging allowing for the first time to reveal the dynamics of endogenous proteins at ultra-high density. Using single protein tracking to study synaptogenic adhesion proteins in neurons, he demonstrated that, like integrins, Neuroligin is a ligand-activated adhesion molecule and that its tyrosine phosphorylation controls the formation of inhibitory and excitatory synapses.

Since January 2016, Grégory Giannone is leading the new group ‘Spatiotemporal and mechanical control of motile structures’. Using super-resolution imaging and single protein tracking his group unraveled the key spatiotemporal molecular events leading to integrins activation by their activators in adhesion sites. In collaboration with the Weaver Group (UCSF, USA), they demonstrated that the mechanical constraints of the glycocalyx in cancerous cells control integrin activation. Using the same approaches his group studied the nanoscale dynamic organization of F-actin regulators in neuronal dendritic spines. They showed that within spines branched F-actin nucleation occurs at the PSD vicinity, while elongation occurs at membrane protrusion tips. This organization is opposite to classical lamellipodial protrusive structures where branched F-actin nucleation and elongation occur at protrusion tips.

Research Associate: Olivier Rossier

Olivier Rossier is a physical chemist by training. Under the supervision of Françoise Brochard-Wyart at the Institut Curie in Paris, he received in 2003 a PhD in soft condensed matter physics studying the dynamics and mechanics of membrane lipidic nanotubes under hydrodynamic flows.

He then decided to complete his interdisciplinary training by joining Michael Sheetz’s lab at Columbia University (2003-2009) to discover the exciting field of mechanobiology. There he started studying the role of membrane tension during integrin-mediated cell spreading and showed that cell spreading induced the exocytosis of specific lipidic pools to decrease plasma membrane tension . Since his post-doctoral years in the laboratory of Michael P. Sheetz, Olivier has been studying the cellular biophysics of integrin-mediated cell spreading, adhesion and force generation using tools emerging from physics (optical tweezers, PDMS micropillars, ...) and chemistry (micro-patterning, soft lithography, …). With this strategy at the interface between biology and physics, he explained how actomyosin contractile forces control turnover of actin networks needed to maintain stable bridges from one adhesive region to another.

Since 2009, he joined the group of Grégory Giannone to apply super-resolution imaging and innovative single protein tracking methods to reveal the nanoscale dynamics and organization of integrin receptors within cell adhesion sites. Since his recruitment at INSERM in 2013, using his expertise in physical-chemistry and biophysics, he is developing studies on mechano-transduction in integrin-based cell adhesions .