- Alexander von Appen
- Jan Brugués
- Dye / Eaton
- Anne Grapin-Botton
- Stephan Grill
- Pierre Haas
- Alf Honigmann
- Meritxell Huch
- Wieland Huttner
- Anthony Hyman
- Florian Jug
- Elisabeth Knust
- Moritz Kreysing
- Rita Mateus
- Carl Modes
- Gene Myers
- André Nadler
- Gaia Pigino
- Jonathan Rodenfels
- Ivo Sbalzarini
- Andrej Shevchenko
- Jacqueline Tabler
- Dora Tang
- Pavel Tomancak
- Agnes Toth-Petroczy
- Jesse Veenvliet
- Christoph Zechner
- Marino Zerial
Our projects can be divided into two main groups:
2. MECHANICS: how physical interactions of cells with each other and their boundaries regulates tissue growth and morphogenesis.
II. CELL AND TISSUE MECHANICS
Anyone who watches a movie of a developing embryo is immediately struck by the dramatic choreography of tissue movements and shape changes and appreciates intuitively that growth and morphogenesis depend on organized physical forces exerted by cells. Epithelial cells, like those in mesenchymal tissues, can sense and exert forces where they contact the extracellular matrix. They can also sense and exert forces cells on each other through their apico-lateral contacts. How do epithelial cells polarize their force generating molecular machinery and remodel their contacts to drive oriented tissue growth and morphogenesis? How do cells respond under force from their neighbors or surroundings? How is the behavior of thousands of cells coordinated to robustly create a tissue with the correct proportions during development? And, central to our overall research focus, how do the patterning systems like Hedgehog influence dynamic cellular behavior and force generation to influence tissue morphogenesis?
Toward this end, one long-standing focus of the lab has been on the role of planar cell polarity (PCP) proteins in tissue morphogenesis. PCP proteins are groups of interacting proteins that polarize intracellularly within the epithelial plane, forming large, tissue-scale patterns that are required to globally orient structures such as hairs on the wing blade or mouse epidermis. Such proteins have also been implicated in orchestrating the morphogenetic events that occur during tissue development, but precisely how this works is unclear. How are the mechanical forces required to shape a tissue coordinated with tissue-scale cell polarity patterns? How do PCP proteins influence force generation or the response of the cell and tissue to externally applied forces?
We are exploring these questions using quantitative image analysis, combined with genetic and physical perturbations. We also work in tight collaboration with the group of Frank Julicher at the MPI-PKS to develop physical models and novel quantitative approaches.
Decomposition of tissue deformation into cellular events: TissueMiner
Tissue deformation results from the summation of cellular activity. In epithelial tissues, cells can divide, extrude, change their neighbors, or change their shape. To study what regulates collective cell behavior during morphogenesis, we need to be able to quantify where and how much these events occur in the tissue over time. Our group created a method to do so, effectively bridging the cellular and tissue scales of biological organization. We created an open source software called TissueMiner for visualizing spatial patterns of cellular activity during long-term timelapse imaging and quantitatively decomposition tissue shape into its contributions from each type of cellular event.
The dynamics and mechanics of epithelial tissue growth
To study tissue growth, we use the Drosophila larval wing imaginal disc as a model. This tissue has long been used to investigate morphogen signaling, and we continue to use it for this purpose. In addition, however, its relatively simple flat geometry, composed almost exclusively of epithelial cells, makes it amenable to high resolution microscopy and 2D physical modeling. While much is known about its patterns of signaling, the dynamics and mechanics of wing growth has been relatively unclear.
Using a combination of theory and experiment, we have shown how the physical properties of the cells within a growing epithelium can explain the geometry of cell packing patterns. We also predicted from theory that a PCP pattern could become globally aligned if the pattern emerged early in development and grew with the tissue. Indeed, we found in the wing that PCP systems become globally aligned early during growth and are influenced by the direction of tissue growth. More recently, we have performed long-term timelapse imaging and decomposed tissue growth into cellular contributions. We found an unexpected role for the boundary in coordinating cellular events, and we are now investigating the nature of such a boundary. We are also now exploring how morphogen signaling and PCP systems influence the dynamics and mechanics of wing growth.
Epithelial tissue shape changes during morphogenesis
During tissue development, often tissues go through a phase of reshaping in the absence of growth. We are studying these phases to understand more about how tissues are shaped by the balance of forces generated in response to cell polarity cues and from the surroundings. As one model system, we are using the Drosophila wing at pupal stages. In the pupal wing, one part of the tissue contracts and pulls on the rest of the tissue, causing it to elongate. We have found that such a mechanical stress can actually reorient the global patterns of PCP proteins. In addition, we have identified p120-catenin as a mechanosensitive molecule regulating the viscoelastic behavior of the apical cell network that controls the timing of this morphogenesis event. Now, we want to know, what affect do PCP proteins have on this morphogenesis? Might they help to coordinate the active response of the tissue to the stress generated during tissue remodeling?
More recently, we have begun expanding our approach into 3D remodeling tissues. Specifically, we are focusing on how tissues undergo dramatic transitions in 3D during morphogenesis. To do so, we are studying the eversion of the Drosophila larval wing disc, when the flattened sac unfolds and turns itself inside out to form a flat bilayer at the transition from larval to pupal stages. We are also now exploring human cell culture systems to study self-organized morphogenesis coupled to fate specification.
Iyer, K. V., Piscitello-Gómez, R., Paijmans, J., Jülicher, F., & Eaton, S. (2019). Epithelial Viscoelasticity Is Regulated by Mechanosensitive E-cadherin Turnover. Current Biology, 29(4), 578-591.e5. https://doi.org/10.1016/j.cub.2019.01.021
Sui, L., Alt, S., Weigert, M., Dye, N., Eaton, S., Jug, F., Myers, E. W., Jülicher, F., Salbreux, G., & Dahmann, C. (2018). Differential lateral and basal tension drive folding of Drosophila wing discs through two distinct mechanisms. Nature Communications, 9(1), 4620. https://doi.org/10.1038/s41467-018-06497-3
Dye, N. A., Popović, M., Spannl, S., Etournay, R., Kainmüller, D., Ghosh, S., Myers, E. W., Jülicher, F., & Eaton, S. (2017). Cell dynamics underlying oriented growth of the Drosophila wing imaginal disc. Development, 144(23), 4406–4421. https://doi.org/10.1242/dev.155069
Jülicher, F., & Eaton, S. (2017). Emergence of tissue shape changes from collective cell behaviours. In Seminars in Cell and Developmental Biology (Vol. 67, pp. 103–112). Elsevier Ltd. https://doi.org/10.1016/j.semcdb.2017.04.004
Etournay, R., Merkel, M., Popović, M., Brandl, H., Dye, N. A., Aigouy, B., Salbreux, G., Eaton, S., & Jülicher, F. (2016). TissueMiner: A multiscale analysis toolkit to quantify how cellular processes create tissue dynamics. ELife, 5. https://doi.org/10.7554/eLife.14334
Aigouy, Benoit, Umetsu, D., & Eaton, S. (2016). Segmentation and Quantitative Analysis of Epithelial Tissues (pp. 227–239). https://doi.org/10.1007/978-1-4939-6371-3_13
Etournay, R., Popović, M., Merkel, M., Nandi, A., Blasse, C., Aigouy, B., Brandl, H., Myers, G., Salbreux, G., Jülicher, F., & Eaton, S. (2015). Interplay of cell dynamics and epithelial tension during morphogenesis of the Drosophila pupal wing. ELife, 4, e07090. https://doi.org/10.7554/eLife.07090
Merkel, M., Sagner, A., Gruber, F. S., Etournay, R., Blasse, C., Myers, E., Eaton, S., & Jülicher, F. (2014). The balance of prickle/spiny-legs isoforms controls the amount of coupling between core and fat PCP systems. Current Biology, 24(18), 2111–2123. https://doi.org/10.1016/j.cub.2014.08.005
Sagner, A., Merkel, M., Aigouy, B., Gaebel, J., Brankatschk, M., Jülicher, F., & Eaton, S. (2012). Establishment of global patterns of planar polarity during growth of the Drosophila wing epithelium. Current Biology, 22(14), 1296–1301. https://doi.org/10.1016/j.cub.2012.04.066
Aigouy, Benoît et al. (2010). Cell Flow Reorients the Axis of Planar Polarity in the Wing Epithelium of Drosophila. Cell, 142(5), 773–786. https://doi.org/10.1016/j.cell.2010.07.042
Farhadifar, R., Röper, J.-C., Aigouy, B., Eaton, S., & Jülicher, F. (2007). The influence of cell mechanics, cell-cell interactions, and proliferation on epithelial packing. Current Biology : CB, 17(24), 2095–2104. https://doi.org/10.1016/j.cub.2007.11.049
Classen, A.-K., Anderson, K. I., Marois, E., & Eaton, S. (2005). Hexagonal packing of Drosophila wing epithelial cells by the planar cell polarity pathway. Developmental Cell, 9(6), 805–817. https://doi.org/10.1016/j.devcel.2005.10.016
Eaton, S. (2003). Cell biology of planar polarity transmission in the Drosophila wing. In Mechanisms of Development (Vol. 120, Issue 11, pp. 1257–1264). Elsevier Ireland Ltd. https://doi.org/10.1016/j.mod.2003.07.002