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Human Molecular Genetics Advance Access published online on January 6, 2006
Human Molecular Genetics, 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
Received October 13, 2005
Revised December 7, 2005
Accepted December 31, 2005

Article

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

Arianna Nenci 1, Marion Huth 1, Alfred Funteh 2, Marc Schmidt-Supprian 3, Wilhelm Bloch 4, Daniel Metzger 5, Pierre Chambon 5, Klaus Rajewsky 3, Thomas Krieg 2, Ingo Haase 2, and Manolis Pasparakis 1 *

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

* To whom correspondence should be addressed.
Manolis Pasparakis, E-mail: pasparakis{at}embl-monterotondo.it


  Abstract

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 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 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 incontinentia pigmenti.


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