Developmental Mechanobiology
The shape of an animal arises in a species-specific, step-wise fashion during embryonic development. During this sequence of events, collectively referred to as ‘embryo morphogenesis’, the embryo constantly remodels its shape. Our lab is interested in the force-generating mechanisms that drive these stereotypic shape changes. We aim at addressing 1) how molecular-scale forces arise in developing embryos and 2) how molecular-scale forces are converted to embryonic shape changes. Our research operates at the intersection between cell biology, developmental biology and biophysics, and employs quantitative methodology from all these disciplines.
The forces that drive embryo morphogenesis are generated by the cytoskeleton of embryonic cells and mainly arise in the actomyosin cortex: a dense two-dimensional network of cross-linked actin polymers residing directly underneath the plasma membrane (see movies below). By pulling and twisting actin polymers, myosin motors and numerous accessory proteins, can generate active forces within the cortical layer. Tight spatiotemporal regulation of these molecular-scale forces in developing embryos ultimately results in cellular-scale shape changes required for embryo morphogenesis.
We use Caenorhabditis elegans and related nematode species to study how molecular forces generated within the actomyosin layer give rise to morphogenetic shape changes in early embryos. To this end, we combine the strength of C. elegans genetics with time-lapse imaging of early embryos (both at high-resolution and at super-resolution), quantitative image analysis and biophysical modelling.
Movie of cortical actomyosin flows in the C. elegans one-cell embryo. Left: Overlay of fluorescently-labeled actin filaments (white) and regions active RhoA (cyan), whrere the molecular-scale forces that drive cortical flows are generated. Right: Quantification of cortical actomyosin flows using Particle Image Velocimetry (PIV).
Ongoing projects
Formin-dependent active torque generation and embryonic left-right symmetry breaking
All bilateral animals display profound left-right asymmetries in the placement of their internal organs. Organismal left-right asymmetry arises during early embryonic development, and often involves chiral movements of embryonic cells. In C. elegans, this is driven by molecular-scale active torques that arise within the actomyosin cortex. In turn, this results in chiral counter-rotating flows of the cortical surface that can be accurately quantified (see above). We previously showed in C. elegans, that molecular-scale torque generation is dependent on the Diaphanous-like Formin CYK-1, which polymerizes actin filaments at their barbed ends. We now study how molecular Formin activity results in torque generation, and how this facilitates chiral movements of embryonic cells. We perform quantitative, time-lapse microscopy of early embryos expressing fluorescently-labeled actomyosin components and their upstream regulators. By combining targeted genetic perturbations with biophysical methods, we aim to unravel how Formin activity needs to be organised to in order to give rise to active torques, and how these molecular-scale active torques lead to chiral rearrangements of embryonic cells.
The role of cytoskeletal activity in the alignment of the dorsoventral axis with embryo geometry
Proper establishment of the major body axes (anteroposterior, dorsoventral, left-right) is essential for embryonic development. The C. elegans dorsoventral axis is established already during the 2-3 cell stage, and its orientation is defined by the division axis of the AB cell, i.e. the anterior-most cell in the C. elegans 2-cell embryo. Studies in various animals have shown that the interplay between cytoskeletal activity and embryo geometry strongly affects early embryonic division patterns. However, whether and how embryo geometry affects the orientation of the dividing AB cell, and thereby the dorsoventral axis is unknown. To study this we are performing quantitative 3-D live imaging of the cytoskeletal machinery in dividing AB cells of embryos with genetically and mechanically perturbed geometries.