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Published 20 November 2006. doi:10.1083/jcb.200605057
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 4, 661-670
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Article

Lipid defect underlies selective skin barrier impairment of an epidermal-specific deletion of Gata-3



Cristina de Guzman Strong1, Philip W. Wertz3, Chenwei Wang1, Fan Yang1,2, Paul S. Meltzer1,2, Thomas Andl4, Sarah E. Millar4, I-Cheng Ho5, Sung-Yun Pai6, and Julia A. Segre1

1 National Human Genome Research Institute and 2 National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
3 University of Iowa, Iowa City, IA 52242
4 Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104
5 Brigham and Women's Hospital, Division of Rheumatology, Immunology, and Allergy and 6 Dana Farber Cancer Institute and Children's Hospital, Combined Department of Pediatric Hematology-Oncology, Harvard Medical School, Boston, MA 02115

Correspondence to Julia A. Segre: jsegre{at}nhgri.nih.gov

Skin lies at the interface between the complex physiology of the body and the external environment. This essential epidermal barrier, composed of cornified proteins encased in lipids, prevents both water loss and entry of infectious or toxic substances. We uncover that the transcription factor GATA-3 is required to establish the epidermal barrier and survive in the ex utero environment. Analysis of Gata-3 mutant transcriptional profiles at three critical developmental stages identifies a specific defect in lipid biosynthesis and a delay in differentiation. Genomic analysis identifies highly conserved GATA-3 binding sites bound in vivo by GATA-3 in the first intron of the lipid acyltransferase gene AGPAT5. Skin from both Gata-3–/– and previously characterized barrier-deficient Kruppel-like factor 4–/– newborns up-regulate antimicrobial peptides, effectors of innate immunity. Comparison of these animal models illustrates how impairment of the skin barrier by two genetically distinct mechanisms leads to innate immune responses, as observed in the common human skin disorders psoriasis and atopic dermatitis.

Abbreviations used in this paper: CE, cornified envelope; ChIP, chromatin immunoprecipitation; E, embryonic day; K, cytokeratin; Klf4, Kruppel-like factor 4; SC, stratum corneum.


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