Actin cortex mechanics and the morphogenesis of animal cells

Lead Research Organisation: MRC Cell Biology Unit

Abstract

We investigate how animal cells control their shape. Many vital processes in our body rely on precise changes in cell shapes. For example, when a tissue is wounded, cells deform and migrate in order to close the wound. Another example is cell division, where the mother cell deforms and splits itself into two daughter cells. Cell division is central to embryonic development, where one initial cell multiplies and gives rise to an entire organism. Improper control of cell shape can lead to many diseases. A prominent example is cancer, where improper division lead to tumour formation and improper migration leads to metastasis.

As for any other physical object, the shape of a cell is controlled by physics. The cell produces molecules, these molecules form larger structures, which determine the mechanical properties of a cell. It is these global mechanical properties that drive cell deformations.

We combine biology and physics to understand how the cell controls its shape. We investigate the physical properties of cells, and relate them to the molecular processes that control them. This approach is powerful, because diseases, such as cancer, are caused by changes in the molecules but their effects, such as tumour formation, result from changes in global cell mechanics. It is thus essential to understand the physical control of processes like cell migration and division. Our long-term aim is to understand how a wrong control of cell physics leads to pathological conditions.

Technical Summary

The shape of animal cells is primarily determined by the cellular cortex, a cross-linked network of actin and myosin underlying the plasma membrane. The cortex enables the cell to resist and exert forces. As such, it plays a central role during events involving cell deformation, such as division and locomotion, and in the patho-physiology of diseases such as cancer, in which cortical mechanics are often misregulated. Despite its importance, very little is known about cortex composition, regulation, and mechanics. To address these questions, we combine cell and molecular biology experiments, quantitative imaging and theoretical modelling. This interdisciplinary approach allows us to investigate the basic mechanisms of morphogenesis across scales, from molecular players to emerging physical behaviours. The group follows three main research directions.

We investigate cell shape control during cell division. Cell cleavage during cytokinesis relies on a controlled reorganisation of the cortex, which concentrates at the equator where it drives furrow ingression. We have recently shown that even though strong cortical forces are generated at the equator, the cortex remaining at the poles of the cell makes cytokinesis inherently unstable; an imbalance in cortex contractility between the two poles can compromise the accurate positioning of the constriction ring and result in contractile oscillations. A theoretical model based on a competition between cortex turnover and contraction dynamics accurately accounts for the oscillations. Taken together, our findings reveal an inherent instability in the shape of the dividing cell, indicating that polar cortex contractility must be tightly controlled during cytokinesis. When this control fails, the cortex displays oscillatory instabilities. We are now exploring how cell mechanics are regulated during cell division in order to ensure stable and symmetric cleavage. Furthermore, we started investigating whether contractile oscillations displayed by the apical cortex during epithelial tissue morphogenesis are driven by a similar mechanism.

We also study cell shape mechanics during migration, with a particular focus on the formation and function of blebs, cellular protrusions driven by cortex contractions. Blebs are a common alternative to lamellipodia during migration in 3-dimensional environments. We are investigating the specific contributions of blebs and lamellipodia to cell motility in culture cells and in vivo, during zebrafish gastrulation. Furthermore, we are exploring the physical mechanisms of cell translocation during bleb-based migration, which seems to occur without specific adhesions to the substrate. To this aim, we use microfluidics channels, which present a well-defined geometry, allowing for quantitative measurements of cell shape and cortex dynamics during migration.

Finally, we are investigating how cortical physical properties are controlled at the network level. As the cortex is less than 300 nm thick, close to the resolution limit of a standard optical microscope, the spatial organisation of cortical components has been elusive. We have developed methods to probe cortex organisation using sub-resolution image analysis. We are investigating the thickness of the cortex and the localisation of essential components, such as myosin motors. Our long-term aim is to understand how cortical contractility is controlled at the molecular level, in healthy and pathological conditions.

People

ORCID iD

Publications

10 25 50
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Bergert M (2015) Force transmission during adhesion-independent migration. in Nature cell biology

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Berthoumieux H (2014) Active elastic thin shell theory for cellular deformations in New Journal of Physics

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Bovellan M (2014) Cellular control of cortical actin nucleation. in Current biology : CB

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Chugh P (2017) Actin cortex architecture regulates cell surface tension. in Nature cell biology

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Clark AG (2013) Monitoring actin cortex thickness in live cells. in Biophysical journal

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Clark AG (2014) Stresses at the cell surface during animal cell morphogenesis. in Current biology : CB

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Paluch EK (2013) The role and regulation of blebs in cell migration. in Current opinion in cell biology

 
Description EU Innovative Training Network
Amount £181,221 (GBP)
Funding ID 641639 ITN BIOPOL 
Organisation Marie Sklodowska-Curie Actions 
Sector Charity/Non Profit
Country Global
Start 01/2015 
End 12/2018
 
Description European Research Council starting grant
Amount € 1,500,000 (EUR)
Funding ID 311637 
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 03/2013 
End 02/2018
 
Description HFSP Young Investigator Grant
Amount $400,000 (USD)
Funding ID RGY0066/2013 
Organisation Human Frontier Science Program (HFSP) 
Sector Charity/Non Profit
Country France
Start 10/2013 
End 09/2016
 
Description Philip Leverhulme Prize in Biological Sciences
Amount £100,000 (GBP)
Organisation The Leverhulme Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 10/2019
 
Title Cortex thickness analysis (dual colour confocal method) 
Description Software for cell segmentation and extraction of cortical linescans for the measurement of cortical thickness. 
Type Of Material Data analysis technique 
Year Produced 2017 
Provided To Others? Yes  
Impact The software its publicly available and has already been used by other groups. In our lab it has been used in two publications: Clark et al, Biophys J 2013 and Chugh et al, Nat Cell Biology 2017 
URL https://github.com/PaluchLabUCL/CortexThicknessAnalysis
 
Description HFSP collaboration 
Organisation National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS)
Department UPR 3082
Country France 
Sector Academic/University 
PI Contribution I have since 2008 a HFSP Young Investigator grant with groups in these three organisations. The grant has recently been renewed for another 4 year period. My laboratory contributes expertise in cellular mechanics, quantitative imaging and modelling.
Collaborator Contribution The group of G Charras contributes expertise on the cell cortex and its regulation, the group of P Roux expertise on mass spectrometry and the group of G Romet-Lemonne, expertise in in vitro studies of actin.
Impact Common publications resulting from the collaboration since 2013 (PMIDs): 24136886; 25017211; 25774834 Other related publications from individual groups: 21630140; 22786929; 22923438; 21980262; 23790388; 23345594; 24845681
Start Year 2008
 
Description HFSP collaboration 
Organisation University College London
Department London Centre for Nanotechnology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have since 2008 a HFSP Young Investigator grant with groups in these three organisations. The grant has recently been renewed for another 4 year period. My laboratory contributes expertise in cellular mechanics, quantitative imaging and modelling.
Collaborator Contribution The group of G Charras contributes expertise on the cell cortex and its regulation, the group of P Roux expertise on mass spectrometry and the group of G Romet-Lemonne, expertise in in vitro studies of actin.
Impact Common publications resulting from the collaboration since 2013 (PMIDs): 24136886; 25017211; 25774834 Other related publications from individual groups: 21630140; 22786929; 22923438; 21980262; 23790388; 23345594; 24845681
Start Year 2008
 
Description HFSP collaboration 
Organisation University of Montreal
Department Institute of Research in Immunology and Cancer (IRIC)
Country Canada 
Sector Academic/University 
PI Contribution I have since 2008 a HFSP Young Investigator grant with groups in these three organisations. The grant has recently been renewed for another 4 year period. My laboratory contributes expertise in cellular mechanics, quantitative imaging and modelling.
Collaborator Contribution The group of G Charras contributes expertise on the cell cortex and its regulation, the group of P Roux expertise on mass spectrometry and the group of G Romet-Lemonne, expertise in in vitro studies of actin.
Impact Common publications resulting from the collaboration since 2013 (PMIDs): 24136886; 25017211; 25774834 Other related publications from individual groups: 21630140; 22786929; 22923438; 21980262; 23790388; 23345594; 24845681
Start Year 2008
 
Description Salbreux group 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Dr Salbreux is a theoretical physicist working in the field of biological physics. We have several ongoing projects combining experiments, quantitative imaging and modelling. The experimental side is provided by my research group.
Collaborator Contribution The group of Dr Salbreux provides their expertise in theoretical physics and modelling of biological systems.
Impact Common articles since 2013: PMIDS: 23452600; 24845681; 25774834; 27589901 Several articles are currently submitted / being prepared.
Start Year 2006
 
Title Cortex thickness analysis (dual colour confocal method) 
Description Software for cell segmentation and extraction of cortical linescans for the measurement of cortical thickness. 
Type Of Technology Software 
Year Produced 2013 
Impact The software its publicly available and has already been used by other groups. In our lab it has been used in two publications: Clark et al, Biophys J 2013 and Chugh et al, Nat Cell Biology 2017 
 
Description MRC Centenary Open Day at UCL 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact activities aiming at explaining cell mechanics to a broader audience. Activities with soap bubbles to mimic cell tension and play-doh model of the cell for children.

enthusiastic feedback from the public on the open day
Year(s) Of Engagement Activity 2013