Abstract
Wound healing is an essential homeostatic mechanism that maintains the epithelial barrier integrity after tissue damage. Although we know the overall steps in wound healing, many of the underlying molecular mechanisms remain unclear. Genetically amenable systems, such as wound healing in Drosophila imaginal discs, do not model all aspects of the repair process. However, they do allow the less understood aspects of the healing response to be explored, e.g., which signal(s) are responsible for initiating tissue remodeling? How is sealing of the epithelia achieved? Or, what inhibitory cues cancel the healing machinery upon completion? Answering these and other questions first requires the identification and functional analysis of wound specific genes. A variety of different microarray analyses of murine and humans have identified characteristic profiles of gene expression at the wound site, however, very few functional studies in healing regulation have been carried out. We developed an experimentally controlled method that is healing-permissive and that allows live imaging and biochemical analysis of cultured imaginal discs. We performed comparative genome-wide profiling between Drosophila imaginal cells actively involved in healing versus their non-engaged siblings. Sets of potential wound-specific genes were subsequently identified. Importantly, besides identifying and categorizing new genes, we functionally tested many of their gene products by genetic interference and overexpression in healing assays. This non-saturated analysis defines a relevant set of genes whose changes in expression level are functionally significant for proper tissue repair. Amongst these we identified the TCP1 chaperonin complex as a key regulator of the actin cytoskeleton essential for the wound healing response. There is promise that our newly identified wound-healing genes will guide future work in the more complex mammalian wound healing response.
Highlights
Damage to an organism initiates a cascade of events that includes inflammation and the formation and remodeling of new tissue
Two major challenges in our understanding of epithelial repair and regeneration is the identification of the signals triggered after injury and the characterization of mechanisms initiated during tissue repair
A key question that remains unanswered is “Why do some wounds fail to heal?” Considering the low genetic redundancy of Drosophila and its high degree of conservation of fundamental functions, the analysis of wound closure in imaginal discs, whose features are comparable to other post-injury events, seems to be a good model
Summary
Damage to an organism initiates a cascade of events that includes inflammation and the formation and remodeling of new tissue. Co-assembly of actin cables and filopodial protrusions are instrumental in all these processes, with the majority being dependent on signaling by the JNK cascade [3, 6,7,8,9]. Healing of incisional wounds in Drosophila adults proceeds through a JNK dependent, lamellipodial-directed, epidermal cell spreading and scab formation [12]. Similar to vertebrate early embryos, Drosophila embryos wounded by laser beams accumulate an actomyosin cable at the leading edge and display dynamic filopodial protrusions. The cable pulls the wound margins like a purse-string and assembles in response to different signaling events, including the activity of the JNK pathway [3, 13]
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