Grose, Richard Philip; (1999) The molecular basis of embryonic wound repair. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Embryonic wound repair is both rapid and perfect. In this thesis, I describe my studies investigating the molecular mechanisms underlying this process. I report my experiments searching for genes which are upregulated at the wound site in a mouse embryo model, and explore the hypothesis that the cellular and molecular mechanisms that underlie tissue repair are the same ones that drive natural morphogenetic tissue movements. My studies have focussed on two animal models: the E11.5 mouse embryo and the Drosophila embryo. In the mouse I have used two approaches to identify "wound-induced" genes (WIGs) upregulated in response to wounding: 1. An informed guesswork approach, looking for expression of genes which seem likely candidates for upregulation at the wound site; and 2. A subtractive hybridisation approach, to identify unknown WIGs. My predictive approach reveals a dramatic upregulation of the zinc-finger transcription factors krox-20 and krox-24, within minutes of wounding, following an identical timecourse of expression as c-fos, the first embryonic WIG ever identified. My subtractive search reveals a number of exciting WIGs, including a protective antioxidant. Non-selenium glutathione peroxidase, which has previously been identified in a cell-based search for wound genes. Alongside these mouse studies, I have characterised two wound healing models in the fruitfly, Drosophila melanogaster: one in late stage embryos and the other in wing imaginal discs. I have shown that the tissue movements of morphogenesis, particularly dorsal closure, and wound repair are remarkably similar, both in their gross appearance and the cytoskeletal machinery they employ. I have demonstrated that Drosophila embryos and imaginal discs use exactly the same cytoskeletal machinery to close a wound as vertebrate embryos, assembling a contractile actin cable within minutes of wounding, suggesting that mechanisms of embryonic wound repair are remarkably well conserved. I have also shown that it is possible to investigate gene expression at the wound site in imaginal discs, and serendipitously struck upon another wound healing model in the larval epidermis, where the tissue polarity gene Dfz2, a homologue of which was identified in my mouse wound subtractive screen, is shown to be upregulated following wounding. The characterisation of the Drosophila wound models described in this thesis will allow further genetic dissection of the molecular events governing wound repair, in a genetically tractable model. These future studies will allow us to determine whether the cellular and molecular tools facilitating tissue repair are indeed the same ones that drive natural morphogenetic tissue movements in the embryo.

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