Tissue Architecture and Plasticity
Group leader : T. Lecuit
We study how epithelial tissues maintain a robust organisation and extensively remodel as they grow and change their shape during development.
Epithelia form mechanical and chemical barriers that are both structurally robust and constantly remodelled during embryogenesis and organogenesis from nematodes to humans. Perturbations in this balance underlie solid cancer progression. How this is controlled is a fundamental unanswered question in biology. Our major ambition is to understand this problem using interdisciplinary approaches that combine the most quantitative analyses with physiological studies in whole organisms. We decipher the biochemical underpinnings of cell and tissue mechanics, namely how forces are generated and how they produce deformations, and characterize their regulation by conserved signalling pathways. Our group requires the complementary expertise of cell and developmental biologists, physicists and engineers etc.
One of the most remarkable properties of living tissues is that they combine robustness in their organisation, and extensive plasticity in their dynamics. This is especially true in epithelial sheets, where cells are usually (but not always) arranged in monolayers. Through the tight association between cells mediated by adhesion molecules, in particular E-cadherin, cells are cohesive and allow the formation of epithelial barriers that separate different physiological environments and protect the organism against pathogens. Epithelia also extensively remodel during development, and in the adult. For instance, epithelia grow and produce new cells via cell division. Cells remodel their contacts and move with respect to each other and contribute to the remodelling of the tissue.
Through these remodelling events, tissues acquire complex shapes and maintain their final organization as new cells replace dead cells.
Tissue robustness requires adhesion mediated by E-cadherin complexes. Plasticity is an active process driven by actomyosin contractility whereby cells remodel their contacts. These forces are transmitted at the cell contacts by E-cadherin complexes.
We address the following major questions:
- how forces emerge from interactions between motors, actin filaments and crosslinker.
- How E-cadherin complexes control adhesion and force transmission.
- How intercellular developmental signals control cell mechanics to drive tissue extension and invagination.
- How cell division and tissue growth affect tissue mechanics and vice versa.
We use the fruitfly Drosophila to address these problems. The major components of cell mechanics and their regulation are shared with humans and this organism lends itself to a very powerful combination of functional, molecular and physical approaches. Our group is largely interdisciplinary and employs a large battery of experimental methods ranging from biochemistry, to genetics, quantitative imaging and modelling.
The morphogenesis of animals has fascinated scientists for decades. Embryologists, geneticists, cell biologists and now physicists have considerably advanced our understanding of how multicellular organisms are formed. There are 3 major trends in the study of morphogenesis. A longstanding interest for the spatial control of cell identity/behaviour led to the identification of general principles of how information flow organizes morphogenesis. The cell biological foundation of morphogenesis emerged gradually and exploded 10 years ago with the advent of live imaging. The cell shape changes that underlie tissue invagination and extension were characterized: apical constriction, cell intercalation. Cell morphogenesis requires force generation and its spatial control by specific biochemical pathway. A more recent trend, fostered by a quantitative description of cell dynamics allows a quantitative/physical understanding of morphogenesis. The field of tissue morphogenesis is thus a broadly expanding and active, interdisciplinary research area.
Research in Drosophila is at the forefront of our understanding of how biochemical pathways control cell mechanics and cell shape changes driving epithelial morphogenesis. Tissue elongation and invagination are two universal classes of tissue shape changes that drive gastrulation. Invagination of the mesoderm, on the ventral half of the embryo, has served as a paradigm for epithelial invagination driven by apical cell constriction. Similar processes drive neural tube closure in vertebrates, and invagination of the endoderm in nematodes, ascidians etc. Apical constriction requires apical Myosin-II (MyoII) phosphorylation by the kinase ROCK, which itself is activated by the small GTPase Rho1 and upstream GEF, such as RhoGEF2. Extension of the ventral lateral ectoderm called the germband, or germband extension (GBE), has become a paradigm for the study of epithelial extension. This process is driven by spatially ordered neighbour exchanges, or cell intercalation. During intercalation cell junctions are remodelled in a planar polarized manner. This is driven by the polarized enrichment of Myosin-II cables in ‘shrinking’, so called ‘vertical’ junctions (Fig. 1A), and the corresponding reduction in Ecad levels. As in apical constriction, MyoII polarized recruitment is dependent on upstream activation by ROCK, and RhoGEFs such as RhoGEF2(15). Thus, similar biochemical pathways underlie force generation in different morphogenetic processes. Recent studies points to deeper similarities. In apical constriction and cell intercalation, actomyosin networks alternate phases of deformation and stabilization. Cell deformation is driven by actomyosin concentration in medial apical contractile pulses (Fig. 1B). The frequency of pulses may define the speed of deformations. While stabilization is apical in mesoderm cells, it only occurs at shrinking ‘vertical’ junctions in the intercalating ectodermal cells (Fig. 1B, C). This ratchet mechanism emerged as a general feature of epithelial mechanics. Although mesoderm and ectodermal cells display similar pulsatile apical actomyosin contractility, their behaviour is different. In ectoderm cells, actomyosin pulses flow anisotropically, ie. in a planar polarized manner towards shrinking junctions (Fig. 1B). However, in mesoderm cells, pulses do not flow and drive an isotropic deformation (Fig. 1C). The presence or absence of flow is thus a point of developmental bifurcation between constriction (tissue invagination), and intercalation (tissue extension).
These findings lead to a general framework of morphogenesis based on i) spatial control over cell deformation by actomyosin flows and stabilization, and ii) temporal control by contractile pulses.
Open questions : A number of key general questions remain unanswered.
- How is pulsatile contractility by actomyosin networks controlled?
- What underlies the different mechanical properties of stabilizing and deforming actomyosin networks?
- What controls the presence/absence of actomyosin flows and how is the flow oriented?
- How are actomyosin forces transmitted at the cell-cell contacts? Is force transmission by adhesive clusters regulated by actomyosin tension? Does force transmission feedback on force generation?
- What pathways are responsible for the spatial control over cell deformations and cell stabilization? What underlies planar polarization in intercalation? How do cells communicate during this process?
- How are local mechanical properties coordinated between cells to achieve robust tissue deformation?
July 29th, 2013
Oscillation and polarity of E-cadherin asymmetries control actomyosin flow patterns during morphogenesis.
February 11th, 2013
Adhesion disengagement uncouples intrinsic and extrinsic forces to drive cytokinesis in epithelial tissues.
May 1st, 2011
Spatial regulation of Dia and Myosin-II by RhoGEF2 controls initiation of E-cadherin endocytosis during epithelial morphogenesis.
December 23rd, 2010
Planar polarized actomyosin contractile flows control epithelial junction remodelling.
December 1st, 2008
Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis.
June 5th, 2008
A two-tiered mechanism for stabilization and immobilization of E-cadherin.
August 3rd, 2006
Spatial control of actin organization at adherens junctions by a synaptotagmin-like protein Btsz.
June 10th, 2004
Myosin-dependent junction remodelling controls planar cell intercalation and axis elongation.
October 28th, 2003
Trafficking through Rab11 endosomes is required for cellularization during Drosophila embryogenesis.
October 29th, 2013
Principles of E-Cadherin Supramolecular Organization In Vivo.
October 1st, 2013
A global pattern of mechanical stress polarizes cell divisions and cell shape in the growing Drosophila wing disc.
June 7th, 2013
Mechanics of epithelial tissue homeostasis and morphogenesis.
April 5th, 2013
Transcriptional and epigenetic signatures of zygotic genome activation during early drosophila embryogenesis.
March 1st, 2013
Stability and dynamics of cell-cell junctions.
February 1st, 2012
Biomechanical regulation of contractility: spatial control and dynamics.
December 1st, 2011
Nuclear mechanics in differentiation and development.
October 1st, 2011
Cell-to-cell contact and extracellular matrix. Editorial overview.
August 1st, 2011
Microtubule-induced nuclear envelope fluctuations control chromatin dynamics in Drosophila embryos.
March 4th, 2011
Developmental biology. Gradient scaling and growth.
January 1st, 2011
Force generation, transmission, and integration during cell and tissue morphogenesis.
August 1st, 2010
An interview with Thomas Lecuit.
June 1st, 2010
alpha-catenin mechanosensing for adherens junctions.
February 1st, 2010
Lighting up developmental mechanisms: how fluorescence imaging heralded a new era.
December 1st, 2009
Repression of Wasp by JAK/STAT signalling inhibits medial actomyosin network assembly and apical cell constriction in intercalating epithelial cells.
November 1st, 2009
Molecular bases of cell-cell junctions stability and dynamics.
October 1st, 2009
Planar polarity and short-range polarization in Drosophila embryos.
June 26th, 2009
Developmental biology. Phase transition in a cell.
June 26th, 2009
Closing in on mechanisms of tissue morphogenesis.
January 1st, 2009
Current topics in developmental biology. Preface.
July 10th, 2008
Breaking down EMT.
April 2nd, 2008
"Developmental mechanics": cellular patterns controlled by adhesion, cortical tension and cell division.
January 1st, 2008
Imaging cellular and molecular dynamics in live embryos using fluorescent proteins.
November 8th, 2007
Orchestrating size and shape during morphogenesis.
August 1st, 2007
Cell surface mechanics and the control of cell shape, tissue patterns and morphogenesis.
March 21st, 2006
Developmental control of nuclear size and shape by Kugelkern and Kurzkern.
February 1st, 2006
Developmental control of nuclear morphogenesis and anchoring by charleston, identified in a functional genomic screen of Drosophila cellularisation.
July 12th, 2005
Cell adhesion: sorting out cell mixing with echinoid?
March 1st, 2005
Compartmentalized morphogenesis in epithelia: from cell to tissue shape.
January 1st, 2005
Adhesion remodeling underlying tissue morphogenesis.
November 1st, 2004
The fly Olympics: faster, higher and stronger answers to developmental questions. Conference on the Molecular and Developmental Biology of Drosophila.
July 15th, 2004
Junctions and vesicular trafficking during Drosophila cellularization.
August 1st, 2003
Regulation of membrane dynamics in developing epithelia.
March 13th, 2003
Developmental biology: Flowers' wings, fruitflies' petals.
February 1st, 2003