Skip to main content

Thank you for visiting 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.

Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6)


Transcription factor paralogs may share a common role in staged or overlapping expression in specific tissues, as in the Hox family. In other cases, family members have distinct roles in a range of embryologic, differentiation or response pathways (as in the Tbx and Pax families). For the interferon regulatory factor (IRF) family of transcription factors, mice deficient in Irf1, Irf2, Irf3, Irf4, Irf5, Irf7, Irf8 or Irf9 have defects in the immune response but show no embryologic abnormalities1,2,3,4,5,6,7. Mice deficient for Irf6 have not been reported, but in humans, mutations in IRF6 cause two mendelian orofacial clefting syndromes8,9,10, and genetic variation in IRF6 confers risk for isolated cleft lip and palate11,12,13,14,15. Here we report that mice deficient for Irf6 have abnormal skin, limb and craniofacial development. Histological and gene expression analyses indicate that the primary defect is in keratinocyte differentiation and proliferation. This study describes a new role for an IRF family member in epidermal development.

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

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genotypic and phenotypic analysis of mice deficient for Irf6.
Figure 2: Skeletal defects in mice deficient for Irf6.
Figure 3: Histologic and molecular analyses of Irf6-null E17.5 embryos.
Figure 4: Epidermal adhesions and desmosomal structure in Irf6-null embryos.
Figure 5: Expression of stratifin and Ikka in skin from Irf6-null E17.5 embryos.

Accession codes



Gene Expression Omnibus


  1. Matsuyama, T. et al. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell 75, 83–97 (1993).

    Article  CAS  Google Scholar 

  2. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity 13, 539–548 (2000).

    Article  CAS  Google Scholar 

  3. Mittrucker, H.W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).

    Article  CAS  Google Scholar 

  4. Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243–249 (2005).

    Article  CAS  Google Scholar 

  5. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005).

    Article  CAS  Google Scholar 

  6. Holtschke, T. et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307–317 (1996).

    Article  CAS  Google Scholar 

  7. Kimura, T. et al. Essential and non-redundant roles of p48 (ISGF3 gamma) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies. Genes Cells 1, 115–124 (1996).

    Article  CAS  Google Scholar 

  8. 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 

  9. Kayano, S. et al. Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion. J. Hum. Genet. 48, 622–628 (2003).

    Article  CAS  Google Scholar 

  10. Wang, X. et al. Novel mutations in the IRF6 gene for Van der Woude syndrome. Hum. Genet. 113, 382–386 (2003).

    Article  CAS  Google Scholar 

  11. Zucchero, T.M. et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N. Engl. J. Med. 351, 769–780 (2004).

    Article  CAS  Google Scholar 

  12. Blanton, S.H. et al. Variation in IRF6 contributes to nonsyndromic cleft lip and palate. Am. J. Med. Genet. A 137, 259–262 (2005).

    Article  Google Scholar 

  13. Ghassibe, M. et al. Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population. Eur. J. Hum. Genet. 13, 1239–1242 (2005).

    Article  CAS  Google Scholar 

  14. Scapoli, L. et al. Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population. Am. J. Hum. Genet. 76, 180–183 (2005).

    Article  CAS  Google Scholar 

  15. Srichomthong, C., Siriwan, P. & Shotelersuk, V. Significant association between IRF6 820G->A and non-syndromic cleft lip with or without cleft palate in the Thai population. J. Med. Genet. 42, e46 (2005).

    Article  CAS  Google Scholar 

  16. Zambrowicz, B.P. et al. Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells. Nature 392, 608–611 (1998).

    Article  CAS  Google Scholar 

  17. Bailey, C.M. et al. Mammary serine protease inhibitor (Maspin) binds directly to interferon regulatory factor 6: identification of a novel serpin partnership. J. Biol. Chem. 280, 34210–34217 (2005).

    Article  CAS  Google Scholar 

  18. Knight, A.S., Schutte, B.C., Jiang, R. & Dixon, M.J. Developmental expression analysis of the mouse and chick orthologues of IRF6: the gene mutated in Van der Woude syndrome. Dev. Dyn. 235, 1441–1447 (2006).

    Article  CAS  Google Scholar 

  19. 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 

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

    Article  CAS  Google Scholar 

  21. 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 

  22. Richardson, R.J. et al. IRF6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat. Genet. advance online publication 15 October 2006 (doi:10.1038/ng1894).

  23. Fisher, C., Jones, A. & Roop, D.R. Abnormal expression and processing of keratins in pupoid fetus (pf/pf) and repeated epilation (Er/Er) mutant mice. J. Cell Biol. 105, 1807–1819 (1987).

    Article  CAS  Google Scholar 

  24. 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 

  25. 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 

  26. Sugihara, T.M., Kudryavtseva, E.I., Kumar, V., Horridge, J.J. & Andersen, B. The POU domain factor Skin-1a represses the keratin 14 promoter independent of DNA binding. A possible role for interactions between Skn-1a and CREB-binding protein/p300. J. Biol. Chem. 276, 33036–33044 (2001).

    Article  CAS  Google Scholar 

  27. Dornan, D. et al. Interferon regulatory factor 1 binding to p300 stimulates DNA-dependent acetylation of p53. Mol. Cell. Biol. 24, 10083–10098 (2004).

    Article  CAS  Google Scholar 

  28. Qin, B.Y. et al. Crystal structure of IRF-3 in complex with CBP. Structure 13, 1269–1277 (2005).

    Article  CAS  Google Scholar 

  29. Yang, H., Lin, C.H., Ma, G., Baffi, M.O. & Wathelet, M.G. Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators. J. Biol. Chem. 278, 15495–15504 (2003).

    Article  CAS  Google Scholar 

  30. MacPartlin, M. et al. p300 regulates p63 transcriptional activity. J. Biol. Chem. 280, 30604–30610 (2005).

    Article  CAS  Google Scholar 

Download references


The authors wish to acknowledge technical assistance from E. Sweezer, R. Cao, T. Kinney, S. Bullard, H. Mishima and A. Lidral. We also thank K. Walters and J. Shao of the Central Microscopy Research Facility and K. Knudtson of the DNA Core Facility at the University of Iowa. We wish to thank R. Richardson and M. Dixon for sharing results before publication. This work was supported in part by US National Institutes of Health grants DE16215 (J.C.M., B.C.S., M.L., B.Y.), DE13513 (B.C.S.) and DE08559 (J.C.M.).

Author information

Authors and Affiliations



This study was designed by B.C.S., S.K., J.C.M. and B.Y.; phenotype assessment was performed by C.R.I., A.K., K.J.T., M.D. and S.L.G.; genotype assessment was performed by M.I.M. and A.K.; data analysis was performed by S.S. and M.L.; and C.R.I., B.C.S., J.C.M., M.L., A.K. and M.D. contributed to the writing of the paper.

Corresponding author

Correspondence to Brian C Schutte.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Change in gene expression for epidermal differentiation markers in Irf6 wild-type versus null skin. (PDF 55 kb)

Supplementary Table 2

Sequence of PCR primers for genotyping Irf6 gene trap allele. (PDF 38 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ingraham, C., Kinoshita, A., Kondo, S. et al. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nat Genet 38, 1335–1340 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


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