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Patients with epidermolysis bullosa (<jats:styled-content style=\"fixed-case\">EB<\/jats:styled-content>) experience multiple erosions, which breach the epidermal barrier and lead to increased microbial colocalization of wounds, infections and sepsis. The cytoskeletal protein Flightless I (Flii) is a known regulator of both development and wound healing. Using <jats:italic>Flii<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>, <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> and <jats:italic>Flii<\/jats:italic><jats:sup>Tg\/Tg<\/jats:sup> mice, we investigated the effect of altering <jats:italic>Flii<\/jats:italic> levels in embryos and adult mice on the development of the epidermal barrier and, consequently, how this affects the integrity of the skin in EB. <jats:italic>Flii<\/jats:italic> over\u2010expression resulted in delayed formation of the epidermal barrier in embryos and decreased expression of tight junction (TJ) proteins Claudin\u20101 and ZO\u20102. Increased intercellular space and transepidermal water loss was observed in <jats:italic><jats:styled-content style=\"fixed-case\">Flii<jats:sup>Tg<\/jats:sup><\/jats:styled-content><jats:sup>\/Tg<\/jats:sup><\/jats:italic> adult mouse skin, while <jats:italic>Flii<jats:sup>Tg\/Tg<\/jats:sup><\/jats:italic> keratinocytes showed altered TJ protein localization and reduced transepithelial resistance. Flii is increased in the blistered skin of patients with <jats:styled-content style=\"fixed-case\">EB<\/jats:styled-content>, and over\u2010expression of Flii in experimental EBA showed impaired Claudin\u20101 and \u20104 <jats:styled-content style=\"fixed-case\">TJ<\/jats:styled-content> protein expression and delayed recovery of functional barrier post\u2010blistering. Immunoprecipitation confirmed Flii associated with TJ proteins and <jats:italic>in vivo<\/jats:italic> actin assays showed that the effect of Flii on actin polymerization underpinned the impaired barrier function observed in <jats:italic>Flii<jats:sup>Tg\/Tg<\/jats:sup><\/jats:italic> mice. These results therefore demonstrate an important role for Flii in the development and regulation of the epidermal barrier, which may contribute to the impaired healing and skin fragility of EB patients. Copyright \u00a9 2013 Pathological Society of Great Britain and Ireland. 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