Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Fuchs, E. & Raghavan, S. Getting under the skin of epidermal morphogenesis. Nat. Rev. Genet. 3, 199–209 (2002).

    Article  CAS  Google Scholar 

  2. Watt, F.M. Stem cell fate and patterning in mammalian epidermis. Curr. Opin. Genet. Dev. 11, 410–417 (2001).

    Article  CAS  Google Scholar 

  3. Dotto, G.P. Signal transduction pathways controlling the switch between keratinocyte growth and differentiation. Crit. Rev. Oral Biol. Med. 10, 442–457 (1999).

    Article  CAS  Google Scholar 

  4. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001).

    Article  CAS  Google Scholar 

  5. Kondo, S. et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat. Genet. 32, 285–289 (2002).

    Article  CAS  Google Scholar 

  6. Escalante, C.R., Yie, J., Thanos, D. & Aggarwal, A.K. Structure of IRF-1 with bound DNA reveals determinants of interferon regulation. Nature 391, 103–106 (1998).

    Article  CAS  Google Scholar 

  7. Hardman, M.J., Sisi, P., Banbury, D.N. & Byrne, C. Patterned acquisition of skin barrier function during development. Development 125, 1541–1552 (1998).

    CAS  PubMed  Google Scholar 

  8. Benitah, S.A., Frye, M., Glogauer, M. & Watt, F.M. Stem cell depletion through epidermal deletion of Rac1. Science 309, 933–935 (2005).

    Article  Google Scholar 

  9. Guenet, J.L., Salzgeber, B. & Tassin, M.T. Repeated epilation: a genetic epidermal syndrome in mice. J. Hered. 70, 90–94 (1979).

    Article  CAS  Google Scholar 

  10. Herron, B.J. et al. A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice. Nat. Genet. 37, 1210–1212 (2005).

    Article  CAS  Google Scholar 

  11. Li, Q., Lu, Q., Estepa, G. & Verma, I.M. Identification of 14–3-3sigma mutation causing cutaneous abnormality in repeated-epilation mutant mouse. Proc. Natl. Acad. Sci. USA 102, 15977–15982 (2005).

    Article  CAS  Google Scholar 

  12. Takeda, K. et al. Limb and skin abnormalities in mice lacking IKKalpha. Science 284, 313–316 (1999).

    Article  CAS  Google Scholar 

  13. Hu, Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 284, 316–320 (1999).

    Article  CAS  Google Scholar 

  14. Li, Q. et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322–1328 (1999).

    Article  CAS  Google Scholar 

  15. Pellegrini, G. et al. p63 identifies keratinocyte stem cells. Proc. Natl. Acad. Sci. USA 98, 3156–3161 (2001).

    Article  CAS  Google Scholar 

  16. Hermeking, H. et al. 14–3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol. Cell 1, 3–11 (1997).

    Article  CAS  Google Scholar 

  17. Chan, T.A., Hermeking, H., Lengauer, C., Kinzler, K.W. & Vogelstein, B. 14–3-3sigma is required to prevent mitotic catastrophe after DNA damage. Nature 401, 616–620 (1999).

    Article  CAS  Google Scholar 

  18. Lees, M.M., Winter, R.M., Malcolm, S., Saal, H.M. & Chitty, L. Popliteal pterygium syndrome: a clinical study of three families and report of linkage to the Van der Woude syndrome locus on 1q32. J. Med. Genet. 36, 888–892 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Dixon, J. et al. Tcof1/Treacle is required for neural crest stem cell formation and proliferation through its role in mature ribosome production, deficiencies in which cause craniofacial abnormalities. Proc. Natl. Acad. Sci. USA 103, 13403–13408 (2006).

    Article  CAS  Google Scholar 

  20. Ghassibe, M. et al. Six families with Van der Woude and/or popliteal pterygium syndrome: all with a mutation in the IRF6 gene. J. Med. Genet. 41, e15 (2004).

    Article  CAS  Google Scholar 

  21. Ingraham, C.R. et al. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nat. Genet. advance online publication 15 October 2006 (doi:10.1038/ng1903).

  22. Mills, A.A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999).

    Article  CAS  Google Scholar 

  23. Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).

    Article  CAS  Google Scholar 

  24. Koster, M.I., Kim, S., Mills, A.A., DeMayo, F.J. & Roop, D.R. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 18, 126–131 (2004).

    Article  CAS  Google Scholar 

  25. Sil, A.K., Maeda, S., Sano, Y., Roop, D.R. & Karin, M. IκB Kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428, 660–664 (2004).

    Article  CAS  Google Scholar 

  26. Wallin, J. et al. The role of Pax-1 in axial skeleton development. Development 120, 1109–1121 (1994).

    CAS  PubMed  Google Scholar 

  27. Mooney, L.M. & Whitmarsh, A.J. Docking interactions in the c-Jun N-terminal pathway. J. Biol. Chem. 279, 11843–11852 (2004).

    Article  CAS  Google Scholar 

  28. Inman, C.K., Li, N. & Shore, P. Oct-1 counteracts autoinhibition of Runx2 DNA binding to form a novel Runx2/Oct-1 complex on the promoter of the mammary gland-specific gene β-casein. Mol. Cell. Biol. 25, 3182–3193 (2005).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Michael J Dixon.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1894

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing