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Published online December 31, 2007
doi:10.1083/jcb.200706187
The Journal of Cell Biology, Vol. 179, No. 7, 1599-1612
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Sevilla et al.
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Article

 Mice deficient in involucrin, envoplakin, and periplakin have a defective epidermal barrier

Lisa M. Sevilla1, Rachida Nachat1, Karen R. Groot2, John F. Klement3, Jouni Uitto3, Philippe Djian4, Arto Määttä5, and Fiona M. Watt1,6

1 Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, England, UK
2 National Cancer Research Institute, London WC2A 3PX, England, UK
3 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107
4 Unité Propre de Recherche 2228, Centre National de la Recherche Scientifique, Institut Interdisciplinaire des Sciences du Vivant des Saints-Peres, Université Rene Descartes, 75006 Paris, France
5 School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, England, UK
6 Wellcome Trust Centre for Stem Cell Research, Cambridge CB2 1QR, England, UK

Correspondence to Fiona M. Watt: fiona.watt{at}cancer.org.uk

The cornified envelope is assembled from transglutaminase cross-linked proteins and lipids in the outermost epidermal layers and is essential for skin barrier function. Involucrin, envoplakin, and periplakin form the protein scaffold on which the envelope assembles. To examine their combined function, we generated mice deficient in all three genes. The triple knockouts have delayed embryonic barrier formation and postnatal hyperkeratosis (abnormal accumulation of cornified cells) resulting from impaired desquamation. Cornified envelopes form but are ultrastructurally abnormal, with reduced lipid content and decreased mechanical integrity. Expression of proteases is reduced and the protease inhibitor, serpina1b, is highly upregulated, resulting in defective filaggrin processing and delayed degradation of desmoglein 1 and corneodesmosin. There is infiltration of CD4+ T cells and a reduction in resident {gamma}{delta}+ T cells, reminiscent of atopic dermatitis. Thus, combined loss of the cornified envelope proteins not only impairs the epidermal barrier, but also changes the composition of T cell subpopulations in the skin.

L.M. Sevilla and R. Nachat contributed equally to this paper.

Abbreviations used in this paper: CE, cornified envelope; E, embryonic day; HET, heterozygous; KO, knockout; P, postnatal day; WT, wild type.


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