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Molecular and Cellular Mechanisms Promoting Single-Cell Migration in vivo

Final Report Summary - CELLMIG (Molecular and Cellular Mechanisms Promoting Single-Cell Migration in vivo)

The project makes use of a population of cells that migrates within an embryo for better understanding of the process of cell migration. The cell population is called "primordial germ cells" and the gonad they generate sperm and egg. In different animals this cell population migrates from one point in the embryo towards the gonad and in this project the cells were investigated in the context of the zebrafish embryo. The reason for choosing this model is the fact that in this case the embryos develop outside the body of the female and the embryos are translucent, facilitating detailed microscopy analysis. Second, as the mechanism of germ cells migration is similar to that of many cancer cells, making them an especially attractive research subject due to their clinical relevance.
The aim to the work was to determine the mechanisms that allow the cells to move from place to place, an important question for understanding how embryos develop, how immune cells migrate to protect the body, how tissues regenerate etc. This issue is also highly important for understanding of related pathological conditions such as cancer metastasis and inflammation when cell migration is not well regulated.
The results of the research provide understanding of how cells move relative to other cells in their environment, how they invade tissues and what maintains or confines them to certain areas in the body.
Specific findings and result of a screen for molecules important for cell migration highlight the importance of proteins called G-proteins. We could show that a specific protein belonging to this family (RGS14) controls the timing of the migration. Related to that, Gbeta/gamma signalling was shown to regulate the response to the directional cue, such that the cells move towards attractant molecules. These findings were followed by identification of the molecules and activities actually needed for allowing cell movement. Here we found that contractile activity, adhesion of the cells to other cells and the level of proteins that connect the membrane to actin are important for the generation of protrusions, the flow of cytoplasm into the protrusion and for movement relative to other cell types. Studying the pathways allowing the actual polarisation of the cells, we focus on the activity of an enzyme called Carbonic anhydrase. This protein is required for the generation of a pH gradient in response to the polarised signal, facilitating actin polymerisation at the cell front. Interestingly, the mechanism by which this enzyme confers polarity involves the generation of a pH gradient along the front/back axis of the cell. A cellular structure identified as important for the structure The requirement rapid progression through the cell cycle stems from the fact that as cells migrate they lose polarity and stop their migration. The identification of proteins involved in controlling the pH within the cells represent another requirement for proteins that regulate this parameter within the cell. This finding is especially interesting with respect to the establishment of cell polarity, as it provides the basis for previously described polarity of structures within migrating cells such as actin. In addition, the morphological analysis of cells and the analysis of cytoplasm flow within them led to new understanding of the process of polar protrusion formation at the cell front. The results of this effort point at folds within the membrane that unfold upon myosin contraction and cytoplasmic flow, thereby providing membrane material to the inflating protrusion.
Together, these findings and understanding has a strong impact on future basic research and on the definition of targets future drugs and treatments should affect in order to interfere with the process in case of pathological scenarios involving cell migration.