Wood, William Jonathan; (2003) Wound healing recapitulates morphogenesis: A genetic study in Drosophila. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The tissue repair movements of embryonic and adult wound healing appear to bear significant similarities to several natural morphogenetic movements that occur throughout embryogenesis across different phyla. In the fruitfly, Drosophila melenogaster, the natural tissue movement that most resembles embryonic epithelial repair is dorsal closure, a process whereby lateral epidermal sheets sweep dorsally to cover over the extra-embryonic amnioserosa, closing the dorsal side of the embryo. Using laser ablation I have established a model of epithelial repair in the fly embryo and have used this model to analyse analogies between morphogenesis and wound healing. In this thesis I use live confocal microscopy to study the cell shape changes and cytoskeletal rearrangements that drive these two tissue movements. I show that both dorsal closure and epithelial repair are associated with the assembly of several actin based structures in the leading edge epithelial cells, including a circumferential cable and dynamic filopodia and lamellae. By modulating the activities of various members of the Rho family of small GTPases I have been able to test the function of these actin-dependent elements in both dorsal closure and wound healing and have obtained results consistent with the view that both processes use the same filopodial driven adhesion mechanism to fuse two epithelial sheets together. During vertebrate wound healing, a key component of the repair process is the inflammatory response, whereby leukocytes - largely neutrophils and macrophages - are drawn from adjacent blood capillaries and chemotax towards the wound site. In my last experimental chapter I describe the presence of an active inflammatory response to laser ablation in the Drosophila embryo. Within minutes of laser wounding - hemocytes (the fly equivalent of macrophages) can be seen actively migrating towards a wound site and, once at the wound site, these cells begin to rapidly engulf and clear cell debris. I have characterised this response in wild type embryos and have begun to analyse the role of the small GTPase Rac in this important cellular process.

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