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IRF6 and SPRY4 Signaling Interact in Periderm Development.
J Dent Res. 2017 Oct; 96(11):1306-1313.JD

Abstract

Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous (Irf6+/-) mice with transgenic mice that express Spry4 in the basal epithelial layer (TgKRT14::Spry4). While embryos with either of these mutations can have abnormal oral adhesions, using a new quantitative assay, we observed a nonadditive effect of abnormal oral epithelial adhesions in the most severely affected double mutant embryos (Irf6+/-;TgKRT14::Spry4). At the molecular level, the sites of abnormal oral adhesions maintained periderm-like cells that express keratin 6, but we observed abnormal expression of GRHL3. Together, these data suggest that Irf6 and RTK signaling interact in regulating periderm differentiation and function, as well as provide a rationale to screen for epistatic interactions between variants in IRF6 and RTK signaling pathway genes in human orofacial clefting populations.

Authors+Show Affiliations

1 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.1 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.2 Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA.2 Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA.3 Departments of Orofacial Sciences and Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.4 Stowers Institute for Medical Research, Kansas City, MO, USA. 5 Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.3 Departments of Orofacial Sciences and Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.2 Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA. 6 Departments of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28732181

Citation

Kousa, Y A., et al. "IRF6 and SPRY4 Signaling Interact in Periderm Development." Journal of Dental Research, vol. 96, no. 11, 2017, pp. 1306-1313.
Kousa YA, Roushangar R, Patel N, et al. IRF6 and SPRY4 Signaling Interact in Periderm Development. J Dent Res. 2017;96(11):1306-1313.
Kousa, Y. A., Roushangar, R., Patel, N., Walter, A., Marangoni, P., Krumlauf, R., Klein, O. D., & Schutte, B. C. (2017). IRF6 and SPRY4 Signaling Interact in Periderm Development. Journal of Dental Research, 96(11), 1306-1313. https://doi.org/10.1177/0022034517719870
Kousa YA, et al. IRF6 and SPRY4 Signaling Interact in Periderm Development. J Dent Res. 2017;96(11):1306-1313. PubMed PMID: 28732181.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IRF6 and SPRY4 Signaling Interact in Periderm Development. AU - Kousa,Y A, AU - Roushangar,R, AU - Patel,N, AU - Walter,A, AU - Marangoni,P, AU - Krumlauf,R, AU - Klein,O D, AU - Schutte,B C, Y1 - 2017/07/21/ PY - 2017/7/22/pubmed PY - 2017/10/3/medline PY - 2017/7/22/entrez KW - GRHL3 protein KW - Van der Woude syndrome KW - cleft lip with or without cleft palate nonsyndromic KW - oral adhesions KW - popliteal pterygium syndrome KW - receptor protein-tyrosine kinases SP - 1306 EP - 1313 JF - Journal of dental research JO - J Dent Res VL - 96 IS - 11 N2 - Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous (Irf6+/-) mice with transgenic mice that express Spry4 in the basal epithelial layer (TgKRT14::Spry4). While embryos with either of these mutations can have abnormal oral adhesions, using a new quantitative assay, we observed a nonadditive effect of abnormal oral epithelial adhesions in the most severely affected double mutant embryos (Irf6+/-;TgKRT14::Spry4). At the molecular level, the sites of abnormal oral adhesions maintained periderm-like cells that express keratin 6, but we observed abnormal expression of GRHL3. Together, these data suggest that Irf6 and RTK signaling interact in regulating periderm differentiation and function, as well as provide a rationale to screen for epistatic interactions between variants in IRF6 and RTK signaling pathway genes in human orofacial clefting populations. SN - 1544-0591 UR - https://www.unboundmedicine.com/medline/citation/28732181/IRF6_and_SPRY4_Signaling_Interact_in_Periderm_Development_ L2 - https://journals.sagepub.com/doi/10.1177/0022034517719870?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -