Abstract
The epidermis is the largest organ of the body for most animals, and the first line of defense against invading pathogens. A breach in the epidermal cell layer triggers a variety of localized responses that in favorable circumstances result in the repair of the wound. Many cellular and genetic responses must be limited to epidermal cells that are close to wounds, but how this is regulated is still poorly understood. The order and hierarchy of epidermal wound signaling factors are also still obscure. The Drosophila embryonic epidermis provides an excellent system to study genes that regulate wound healing processes. We have developed a variety of fluorescent reporters that provide a visible readout of wound-dependent transcriptional activation near epidermal wound sites. A large screen for mutants that alter the activity of these wound reporters has identified seven new genes required to activate or delimit wound-induced transcriptional responses to a narrow zone of cells surrounding wound sites. Among the genes required to delimit the spread of wound responses are Drosophila Flotillin-2 and Src42A, both of which are transcriptionally activated around wound sites. Flotillin-2 and constitutively active Src42A are also sufficient, when overexpressed at high levels, to inhibit wound-induced transcription in epidermal cells. One gene required to activate epidermal wound reporters encodes Dual oxidase, an enzyme that produces hydrogen peroxide. We also find that four biochemical treatments (a serine protease, a Src kinase inhibitor, methyl-ß-cyclodextrin, and hydrogen peroxide) are sufficient to globally activate epidermal wound response genes in Drosophila embryos. We explore the epistatic relationships among the factors that induce or delimit the spread of epidermal wound signals. Our results define new genetic functions that interact to instruct only a limited number of cells around puncture wounds to mount a transcriptional response, mediating local repair and regeneration.
Highlights
The development of a specialized epidermal barrier layer represents a key step during the evolution of multi-cellular organisms
An epidermal wound provides signals that initiate a variety of localized responses, some of which act to regenerate and repair the breach in the epidermal barrier
Using fluorescent epidermal ‘‘wound’’ reporters that are locally activated around wound sites, we have screened almost 5,000 Drosophila mutants for functions required to activate or delimit wound-induced transcriptional responses to a local zone of epidermal cells
Summary
The development of a specialized epidermal barrier layer represents a key step during the evolution of multi-cellular organisms. This outer integument provides protection from the environment and helps maintain cellular homeostasis. Epidermal barriers consist of epithelial cells that are tightly joined by adherens and other types of junctional complexes, as well an apical extracellular matrix layer that is highly variable. In arthropods like Drosophila melanogaster, a single epidermal cell layer secretes a multilayered matrix of cross-linked lipid, protein, and chitin to generate a largely impermeable cuticle barrier [2,3]. There are many complex processes that contribute to epidermal wound healing; these include clot formation, reepithelialization, cellular proliferation, inflammation, and barrier replacement [8]. Drosophila is a genetically tractable system for discovering evolutionarily conserved genes involved in such epidermal wound healing processes, as it has been for discovering genes that regulate animal septic wound responses [9]
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