Elucidating the interplay between cellular behaviour and tissue mechanics during morphogenesis
Lead Research Organisation:
University of Cambridge
Department Name: Genetics
Abstract
Cells are the building blocks for the tissues and organs that make up organisms. One strategy used by cells in this process is to arrange themselves in sheets, called epithelia, that are then folded into shapes through a kind of molecularly driven bio-oregamy. Epithelia are configured by cells joining each other through specialized attachments called 'junctions'. Cells contain a cellular scaffolding or cytoskeleton that is linked to the 'junctions' and allows them to change and maintain their shape in a controlled manner. Bending and folding these sheets makes organisms and failures in these activities result in deformations or structural defects. For these reasons, it is not surprising that the coordination of the activity of the cytoskeleton and that of the 'junctions' between cells is a crucial element in the folding of the sheets. Over the years, the fruit fly Drosophila has proven an excellent system to unravel the mechanics of animal development. Recently it is also proving a valuable research tool to analyze the activities of groups of cells and the movement and folding of epithelia. Here we plan to use the fly embryo to study the molecular basis of bending, folding and interactions between sheets of cells. We shall do this by combining classical biological techniques anchored in the study of the effects of mutations on a particular process with engineering type analysis of the forces generated by cells at the level of tissues.
Technical Summary
Half way through embryonic development, the epidermis of Drosophila exhibits a gap covered by a squamous epithelium, the amnioserosa. Dorsal closure (DC) is the process whereby interactions between the two epithelia establish epidermal continuity. This process is an excellent model system to study the cellular activities involved in morphogenesis, the set of complex and dynamic interactions between groups of cells that govern the formation of 3D structures, and to correlate them with biophysical properties of the cells. A number of studies suggest that the activities of the cytoskeleton and of the adhesion systems of a cell must be carefully regulated during morphogenesis. Here we propose to study the coordination of these two activities during DC combining classical genetics with biophysical measurements of cellular parameters. The resulting information will be integrated into a finite element model of the process which should inform about emergent properties at the tissue level. Specifically, using state of the art microscopy we shall probe the function of a-catenin that links the Cadherin based adhesion system with the cytoskeleton. In parallel, we shall use laser-ablation of cells and cell boundaries to analyze the dynamic distribution of forces during dorsal closure. This analysis will reveal the dynamic map of tensions that underlies the process and, through a genetic perturbation analysis, will allow us to relate molecular events at the single cell level with tissue behaviour. The data gathered from these analyses will be used to generate a computational simulation of dorsal closure, which will have predictive value, will yield new insights into the nature of morphogenesis through a constructive feedback on the experiments.
Publications
Blanchard GB
(2009)
Tissue tectonics: morphogenetic strain rates, cell shape change and intercalation.
in Nature methods
Mateus AM
(2009)
Origin and function of fluctuations in cell behaviour and the emergence of patterns.
in Seminars in cell & developmental biology
Gorfinkiel N
(2009)
Mechanical control of global cell behaviour during dorsal closure in Drosophila.
in Development (Cambridge, England)
Blanchard GB
(2010)
Cytoskeletal dynamics and supracellular organisation of cell shape fluctuations during dorsal closure.
in Development (Cambridge, England)
Gorfinkiel N
(2011)
Dynamics of actomyosin contractile activity during epithelial morphogenesis.
in Current opinion in cell biology
Description | This project brought out the interaction between mechanical and genetic elements during morphogenesis and allowed the beginning of a description of emergent properties in a developing system. Specifically we showed how the activities of the cytoskeleton at the level of single cells gives rise to the global properties of the tissue. The main postdoc in the grant also made significant contributions to the development of methods to reveal these properties. |
Exploitation Route | One of the main findings concerns the role of the cytoskeleton in the transformation of single cell activities to those of a tissue. This means that the findings could be use to uncover targets for drugs in tissue repair. |
Sectors | Healthcare |
URL | http://www.gen.cam.ac.uk/directory/alfonso-martinez-arias |
Description | image analysis methodology for cell ensembles during morphogenesis |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided the data, the genetics, the interpretation and some of the analysis |
Collaborator Contribution | They provided software and methods for image analysis and modelling of the data |
Impact | Scientific publications |
Title | Human polarized three dimensional cellular aggregates |
Description | Aggregates of defined numbers of human ES cells which, under defined culture conditions undergo gastrulation like movements and generate a mammalian body plan |
IP Reference | GB1815439.3 |
Protection | Patent application published |
Year Protection Granted | 2018 |
Licensed | No |
Impact | None yet beyond discussions following some commercial interest |
Title | Polarized three dimensional cellular aggregates |
Description | Aggregates of defined numbers of mouse ES cells which, under defined culture conditions undergo gastrulation like movements and generate a mammalian body plan. |
IP Reference | GB1815438.5 |
Protection | Patent application published |
Year Protection Granted | 2018 |
Licensed | No |
Impact | There is interest from some pharmaceutical and stem cell companies |