Squeezing through the embryo:Dissecting nuclear mechanics during embryonic cell migration

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Macrophages are highly motile immune cells which often act as the first line of defence against pathogens. They also assist in wound healing and clearing up of dead cells and debris and tissue remodelling. All these functions are extremely important to ensure accurate animal development and homeostasis in the adult. They can also be reprogrammed to act in highly detrimental ways, assisting cancer metastasis and exacerbating inflammation. Since their ability to migrate underpins their ability to function accurately, understanding macrophage migration has important implications to our ability to ensure healthy living across the lifespan. We use the macrophages of the common fruit fly Drosophila Melanogaster as a model system to study macrophage migration. Fruit fly macrophages, also called haemocytes, are very like their vertebrate counterparts; they display similar origins and utilize similar mechanisms to migrate. Our recent work using the fruit fly macrophages in the embryo showed that they can squeeze into very dense tissue environments and this ability to migrate under tight confinement is important to ensure macrophage distribution within the embryo. In this proposal, we address the mechanisms through which the macrophage nucleus is moved through tissue barriers. The nucleus which is the repository of the genetic information also happens to be the stiffest organelle in the cell. Hence, moving the nucleus through barriers is not an easy task and nuclear deformation is key to migration under confinement. We have recently discovered that the macrophage nucleus undergoes extensive rearrangements in shape while they move through the embryo. Using a combination of biophysical and genetic experiments as well as cutting edge image analysis and mathematical modelling, we seek to understand the mechanical forces which are generated and transduced to deform and move the nucleus. We also seek to understand how nuclear deformations can in turn affect gene expression and thus macrophage functionality. We anticipate that fundamental principles which govern nuclear mechanics will be conserved across multiple cell types and the results of our proposal will inform studies not only on macrophage migration, but that of other embryonically migrating cell types and even metastatic cancer cells.