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Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation

Nature Cell Biology volume 9, pages 461–469 (2007)Cite this article

Abstract

The kinase IKK1 (also known as IKKα) was previously reported to regulate epidermal development and skeletal morphogenesis by acting in keratinocytes to induce their differentiation in an NF-κB independent manner1,2,3,4,5. Here, we show that mice with epidermal keratinocyte-specific IKK1 ablation (hereafter referred to as IKK1EKO) develop a normally differentiated stratified epidermis, demonstrating that the function of IKK1 in inducing epidermal differentiation is not keratinocyte-autonomous. Despite normal epidermal stratification, the IKK1EKO mice display impaired epidermal-barrier function and increased transepidermal water loss, due to defects in stratum corneum lipid composition and in epidermal tight junctions. These defects are caused by the deregulation of retinoic acid target genes, encoding key lipid modifying enzymes and tight junction proteins, in the IKK1-deficient epidermis. Furthermore, we show that IKK1-deficient cells display impaired retinoic acid-induced gene transcription, and that IKK1 is recruited to the promoters of retinoic acid-regulated genes, suggesting that one mechanism by which IKK1 controls epidermal-barrier formation is by regulating the expression of retinoic acid receptor target genes in keratinocytes.

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Figure 1: Normal epidermal differentiation in mice with keratinocyte-specific knockout of Ikk1.
Figure 2: IKK1 is essential for epidermal barrier formation.
Figure 3: IKK1 is essential for normal epidermal lipid metabolism.
Figure 4: Loss of IKK1 in the epidermis leads to increased vascularisation.
Figure 5: Impaired retinoic acid-induced transcriptional activity in the absence of IKK1.

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Acknowledgements

We thank J. X. Neto for the retinoic acid reporter constructs, A. Aranda for the GST–CSMRT vector, and T. Krieg and C. Niessen for critical reading of the manuscript. The genomics core facility of the European Molecular Biology Laboratory (EMBL) assisted with the microarray experiments and data submission. This work was supported by the University of Cologne and by EMBL and by EU FP6 grant MUGEN (LSHG-CT-2005-005203) to M. P.

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Authors and Affiliations

  1. Department of Mouse Genetics and Inflammation, Institute for Genetics, University of Cologne, Zülpicher Str. 47, Cologne, 50674, Germany

    Ralph Gareus & Manolis Pasparakis

  2. EMBL Mouse Biology Unit, Via Ramarini 32, Monterotondo Scalo, 00016, Italy

    Ralph Gareus, Marion Huth, Arianna Nenci, Nora Rösch & Manolis Pasparakis

  3. LIMES, Membrane Biology and Lipid Biochemistry Unit, c/o Kekulè-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Str. 1, Bonn, 53121, Germany

    Bernadette Breiden & Konrad Sandhoff

  4. Department of Dermatology, University of Cologne, Joseph-Stelzmann-Str. 9, Cologne, 50924, Germany

    Ingo Haase

  5. Department for Molecular and Cellular Sport Medicine, German Sport University Cologne, Carl-Diem-Weg 6, Cologne, 50933, Germany

    Wilhelm Bloch

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Gareus, R., Huth, M., Breiden, B. et al. Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation. Nat Cell Biol 9, 461–469 (2007). https://doi.org/10.1038/ncb1560

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