Toll/NF-κB signaling pathway is required for epidermal wound repair in Drosophila

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (50), p.E5373-E5382
• Main Authors: Carvalho, Lara, Jacinto, António, Matova, Nina
• Format: Article
• Language: English
• Subjects: Adherens Junctions - metabolism; Animals; Biological Sciences; Blotting, Western; Cadherins - metabolism; Drosophila; Drosophila melanogaster - embryology; Drosophila Proteins - metabolism; Embryo, Nonmammalian - physiology; Epidermis - physiology; Fluorescence; Fluorescence Recovery After Photobleaching; Immunohistochemistry; NF-kappa B - metabolism; PNAS Plus; Real-Time Polymerase Chain Reaction; Signal Transduction - physiology; Toll-Like Receptors - metabolism; Wound Healing - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1408224111

Significance Injury and repair of broken skin are an integral part of human existence, but the ability to heal wounds extends across species. Animals ranging from insects and worms to fish, amphibians, birds, and mammals all protect and restore body integrity. Our study reveals that the evolutionary-conserved Toll/NF-κB signaling pathway, which provides the first line of defense against microbial infection, is crucial for wound repair in the embryonic epidermis (the skin) of the insect Drosophila melanogaster . Toll/NF-κB signaling promotes remodeling of cellular junctions and assembly of a cytoskeletal ring around the wound. Contraction of this ring much like a “purse string” fastens the epidermal gap. The findings set the stage for a similar investigation of the pathway in wound repair in vertebrates. The Toll/NF-κB pathway, first identified in studies of dorsal-ventral polarity in the early Drosophila embryo, is well known for its role in the innate immune response. Here, we reveal that the Toll/NF-κB pathway is essential for wound closure in late Drosophila embryos. Toll mutants and Dif dorsal (NF-κB) double mutants are unable to repair epidermal gaps. Dorsal is activated on wounding, and Dif and Dorsal are required for the sustained down-regulation of E-cadherin, an obligatory component of the adherens junctions (AJs), at the wound edge. This remodeling of the AJs promotes the assembly of an actin-myosin cable at the wound margin; contraction of the actin cable, in turn, closes the wound. In the absence of Toll or Dif and dorsal ( dl ), both E-cadherin down-regulation and actin-cable formation fail, thus resulting in open epidermal gaps. Given the conservation of the Toll/NF-κB pathway in mammals and the epithelial expression of many components of the pathway, this function in wound healing is likely to be conserved in vertebrates.