Abnormal Skin, Limb and Craniofacial Morphogenesis in Mice Deficient for Interferon Regulatory Factor 6 (Irf6)

Overview

Journal Nat Genet

Specialty Genetics

Date 2006 Oct 17

PMID 17041601

Citations 205

Authors

Christopher R Ingraham

Akira Kinoshita

Shinji Kondo

Baoli Yang

Samin Sajan

Kurt J Trout

Margaret I Malik

Martine Dunnwald

Stephen L Goudy

Michael Lovett

Jeffrey C Murray

Brian C Schutte

Affiliations

Soon will be listed here.

Abstract

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 abnormalities. Mice deficient for Irf6 have not been reported, but in humans, mutations in IRF6 cause two mendelian orofacial clefting syndromes, and genetic variation in IRF6 confers risk for isolated cleft lip and palate. 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.

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References

Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K . Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. 2000; 13(4):539-48. DOI: 10.1016/s1074-7613(00)00053-4. View

Richardson R, Dixon J, Malhotra S, Hardman M, Knowles L, Boot-Handford R . Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat Genet. 2006; 38(11):1329-34. DOI: 10.1038/ng1894. View

Kondo S, Schutte B, Richardson R, Bjork B, Knight A, Watanabe Y . Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet. 2002; 32(2):285-9. PMC: 3169431. DOI: 10.1038/ng985. View

Yang H, Lin C, Ma G, Baffi M, Wathelet M . Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators. J Biol Chem. 2003; 278(18):15495-504. DOI: 10.1074/jbc.M212940200. View

Wang X, Liu J, Zhang H, Xiao M, Li J, Yang C . Novel mutations in the IRF6 gene for Van der Woude syndrome. Hum Genet. 2003; 113(5):382-6. DOI: 10.1007/s00439-003-0989-2. View

Kayano S, Kure S, Suzuki Y, Kanno K, Aoki Y, Kondo S . 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. 2003; 48(12):622-628. DOI: 10.1007/s10038-003-0089-0. View

Sil A, Maeda S, Sano Y, Roop D, Karin M . IkappaB kinase-alpha acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature. 2004; 428(6983):660-4. DOI: 10.1038/nature02421. View

Zucchero T, Cooper M, Maher B, Daack-Hirsch S, Nepomuceno B, Ribeiro L . Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004; 351(8):769-80. DOI: 10.1056/NEJMoa032909. View

Dornan D, Eckert M, Wallace M, Shimizu H, Ramsay E, Hupp T . Interferon regulatory factor 1 binding to p300 stimulates DNA-dependent acetylation of p53. Mol Cell Biol. 2004; 24(22):10083-98. PMC: 525491. DOI: 10.1128/MCB.24.22.10083-10098.2004. View

10.

Fisher C, Jones A, Roop D . Abnormal expression and processing of keratins in pupoid fetus (pf/pf) and repeated epilation (Er/Er) mutant mice. J Cell Biol. 1987; 105(4):1807-19. PMC: 2114667. DOI: 10.1083/jcb.105.4.1807. View

11.

Matsuyama T, Kimura T, Kitagawa M, Pfeffer K, Kawakami T, Watanabe N . Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell. 1993; 75(1):83-97. View

12.

Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, Rosenbauer F . Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell. 1996; 87(2):307-17. DOI: 10.1016/s0092-8674(00)81348-3. View

13.

Mittrucker H, Matsuyama T, Grossman A, Kundig T, Potter J, Shahinian A . Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science. 1997; 275(5299):540-3. DOI: 10.1126/science.275.5299.540. View

14.

Kimura T, Kadokawa Y, Harada H, Matsumoto M, Sato M, Kashiwazaki Y . 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. 1996; 1(1):115-24. DOI: 10.1046/j.1365-2443.1996.08008.x. View

15.

Zambrowicz B, Friedrich G, Buxton E, Lilleberg S, Person C, Sands A . Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells. Nature. 1998; 392(6676):608-11. DOI: 10.1038/33423. View

16.

Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M . Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science. 1999; 284(5412):316-20. DOI: 10.1126/science.284.5412.316. View

17.

Scapoli L, Palmieri A, Martinelli M, Pezzetti F, Carinci P, Tognon M . 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. 2004; 76(1):180-3. PMC: 1196422. DOI: 10.1086/427344. View

18.

Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T . Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005; 434(7030):243-9. DOI: 10.1038/nature03308. View

19.

Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T . IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005; 434(7034):772-7. DOI: 10.1038/nature03464. View

20.

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. 2005; 42(7):e46. PMC: 1736106. DOI: 10.1136/jmg.2005.032235. View