title: Fibroblast-specific upregulation of Flightless I impairs wound healing.
abstract: The cytoskeletal protein Flightless (Flii) is a negative regulator of wound healing. Upregulation of Flii is associated with impaired migration, proliferation and adhesion of both fibroblasts and keratinocytes. Importantly, Flii translocates from the cytoplasm to the nucleus in response to wounding in fibroblasts but not keratinocytes. This cell-specific nuclear translocation of Flii suggests that Flii may directly regulate gene expression in fibroblasts, providing one potential mechanism of action for Flii in the wound healing response. To determine whether the tissue-specific upregulation of Flii in fibroblasts was important for the observed inhibitory effects of Flii on wound healing, an inducible fibroblast-specific Flii overexpressing mouse model was generated. The inducible ROSA26 system allowed the overexpression of Flii in a temporal and tissue-specific manner in response to tamoxifen treatment. Wound healing in the inducible mice was impaired, with wounds at day 7 postwounding significantly larger than those from non-inducible controls. There was also reduced collagen maturation, increased myofibroblast infiltration and elevated inflammation. The impaired healing response was similar in magnitude to that observed in mice with non-tissue-specific upregulation of Flii suggesting that fibroblast-derived Flii may have an important role in the wound healing response.
authors.affiliation: Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, SA, Australia.
authors.forename: Christopher T
authors.identifier: http://orcid.org/0000-0001-7409-4386
authors.initials: CT
authors.lastname: Turner
authors.affiliation: Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, SA, Australia.
authors.forename: James M
authors.initials: JM
authors.lastname: Waters
authors.affiliation: Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, SA, Australia.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Jackson
authors.affiliation: Research School of Biological Sciences, Australian National University, Canberra, ACT, Australia.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Arkell
authors.affiliation: Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, SA, Australia.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Cowin
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002352:Carrier Proteins; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000648:ultrastructure; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008840:Microfilament Proteins; D023421:Models, Animal; D011995:Recombination, Genetic / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D015534:Trans-Activators; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000609263:FlII protein, mouse; D008840:Microfilament Proteins; D015534:Trans-Activators; D013629:Tamoxifen; D003094:Collagen
keywords: Flightless I; cytoskeleton; fibroblast; wound