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Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch

Nature Genetics volume 38, pages 1329–1334 (2006)Cite this article

Abstract

The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism1. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population1,2; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive3. Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3σ) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process.

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Figure 1: Phenotype analysis of wild-type (WT) and Irf6+/R84C (Het) mice.
Figure 2: Phenotypic analysis of Irf6R84C/R84C mutant mice.
Figure 3: Analysis of E17 Irf6R84C/R84C mutant epidermis.
Figure 4: Analysis of Sfn and Irf6 in Irf6R84C/R84C and SfnEr/Er mice and IKKα in Irf6R84C/R84C mice.
Figure 5: Phenotype analysis of Irf6+/R84C Sfn+/Er mutant mice.
Figure 6: Analysis of Irf6+/R84C Sfn+/Er mutant epidermis.

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Acknowledgements

We thank J. Murray and B. Schutte (University of Iowa) for providing the antibody to IRF6 and data in advance of publication. We also thank H. Worthington for statistical analysis, D. Clayton for his help with the imaging and the Electron Microscope Facility in the Faculty of Life Sciences, University of Manchester, particularly A. Mironov, for their assistance. This study was supported by grants from the US National Institutes of Health (P50-DE016215) and the Wellcome Trust (064732, 066173).

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Authors and Affiliations

  1. Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    Rebecca J Richardson, Saimon Malhotra, Matthew J Hardman, Lynnette Knowles, Ray P Boot-Handford, Paul Shore, Alan Whitmarsh & Michael J Dixon

  2. Dental School, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    Rebecca J Richardson, Jill Dixon, Saimon Malhotra & Michael J Dixon

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Contributions

R.J.R. generated and analyzed the mutant mice and wrote the paper, J.D. designed experiments and wrote the paper, S.M. and P.S. performed the electrophoretic mobility shift assays, M.J.H. designed experiments, L.K. performed the blastocyst injections, R.P.B.-H. designed experiments, A.W. performed the co-immunoprecipitation experiments and M.J.D. designed experiments and wrote the paper.

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Correspondence to Michael J Dixon.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Gene targeting of the Irf6 locus. (PDF 98 kb)

Supplementary Table 1

Sequences of primers used in the analysis of IRF6. (PDF 69 kb)

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Richardson, R., Dixon, J., Malhotra, S. et al. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat Genet 38, 1329–1334 (2006). https://doi.org/10.1038/ng1894

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