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Human Molecular Genetics Advance Access originally published online on January 6, 2006
Human Molecular Genetics 2006 15(4):531-542; doi:10.1093/hmg/ddi470
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© The Author 2006. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling

Arianna Nenci1, Marion Huth1, Alfred Funteh2, Marc Schmidt-Supprian3, Wilhelm Bloch4, Daniel Metzger5, Pierre Chambon5, Klaus Rajewsky3, Thomas Krieg2, Ingo Haase2 and Manolis Pasparakis1,*

1European Molecular Biology Laboratory, Mouse Biology Unit, via Ramarini 32, 00016 Monterotondo-Scalo (Rome), Italy, 2Department of Dermatology, Center for Molecular Medicine, University of Cologne (CMMC), Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany, 3CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA, 4Abteilung für Molekulare und Zelluläre Sportmedizin, Deutsche Sporthochschule Köln, IG I, Carl-Diem-Weg 6, D-50933 Köln, Germany and 5Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, INSERM, ULP, and Institut Clinique de la Souris (ICS), BP 10142-67404, ILLKIRCH, C.U. de Strasbourg, France

* To whom correspondence should be addressed. Tel: +39 0690091222/90091271; Fax: +39 0690091272; Email: pasparakis{at}embl-monterotondo.it

Received October 13, 2005; Revised December 7, 2005; Accepted December 31, 2005

NF-{kappa}B essential modulator (NEMO), the regulatory subunit of the I{kappa}B kinase, is essential for NF-{kappa}B activation. Mutations disrupting the X-linked NEMO gene cause incontinentia pigmenti (IP), a human genetic disease characterized by male embryonic lethality and by a complex pathology affecting primarily the skin in heterozygous females. The cellular and molecular mechanisms leading to skin lesion pathogenesis in IP patients remain elusive. Here we used epidermis-specific deletion of NEMO in mice to investigate the mechanisms causing the skin pathology in IP. NEMO deletion completely inhibited NF-{kappa}B activation and sensitized keratinocytes to tumor necrosis factor (TNF)-induced death but did not affect epidermal development. Keratinocyte-restricted NEMO deletion, either constitutive or induced in adult skin, caused inflammatory skin lesions, identifying the NEMO-deficient keratinocyte as the initiating cell type that triggers the skin pathology in IP. Furthermore, genetic ablation of tumor necrosis factor receptor 1 (TNFRI) rescued the skin phenotype demonstrating that TNF signaling is essential for skin lesion pathogenesis in IP. These results identify the NEMO-deficient keratinocyte as a potent initiator of skin inflammation and provide novel insights into the mechanism leading to the pathogenesis of IP.


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