We study how epithelial tissues maintain a robust organisation and extensively remodel as they grow and change their shape during development.

FOR BEGINNERS

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.

FOR SPECIALITS

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?