Atopic dermatitis and skin diseaseAltered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice
Section snippets
Generation of Flg−/− mice
Flg, which is located on chromosome 3, consists of 3 exons and shares unique characteristics with its human counterpart. Exon 1 consists of 5′ untranslated region (UTR) sequences, exon 2 contains the translation start site, and the unusually large exon 3 encodes nearly identical filaggrin repeats (see Fig E1, A, in this article’s Online Repository at www.jacionline.org). Large open reading frames and repetitive sequences complicate the strategy by which the genes are targeted. Nevertheless, we
Generation of Flg−/− mice
Flg−/− mice were generated by means of homologous recombination (see the Methods section and Fig E1 in this article’s Online Repository). Mice were backcrossed to both C57BL/6 and BALB/c backgrounds to minimize phenotypic variation. Immunoblotting and immunohistochemical analyses revealed that Flg-targeted mice were completely deficient for both profilaggrin and filaggrin (Fig 1), which is in contrast to ft/ma mice, in which abundant amounts of truncated profilaggrin and low but detectable
Discussion
Filaggrin has been demonstrated to function in SC integrity as a structural protein that organizes keratin filaments.6 It is also a major source of the hygroscopic amino acids in SC referred to as NMFs.8 NMFs are believed to maintain SC hydration levels.8 Although the biology and functions of filaggrin have been modeled through in vitro experiments, its in vivo functions have remained elusive because of the absence of mice that completely and specifically lack filaggrin. This was due to
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Supported by a Health Labour Sciences Research Grant for Research on Allergic Diseases and Immunology from the Ministry of Health, Labour and Welfare of Japan; Grants-in-Aid for Scientific Research; the “Promotion of Environmental Improvement for Independence of Young Researchers” program and a Matching Fund Subsidy for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Research Grants for Life Sciences and Medicine from Keio University Medical Science Fund; and a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists.
Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.