IRF6 expression in basal epithelium partially rescues Irf6 knockout mice. Issue 9 (19th July 2017)

• Record Type: Journal Article
• Authors: Kousa, Youssef A.; Moussa, Dina; Schutte, Brian C.
• Is Part Of: Developmental dynamics. Volume 246:Issue 9(2017)
• Page Start: 670
• Page End: 681
• Publication Date: 2017-07-19
• Subjects: IRF6 -- GRHL3 -- cleft lip and palate -- Van der Woude syndrome -- popliteal pterygium syndrome -- limb defects -- genetic rescue -- mouse models -- epithelium -- epidermis -- oral periderm; Morphogenesis -- Periodicals; Anatomy -- Periodicals; Anatomie -- Périodiques; Biologie du développement -- Périodiques; 571.833
• DOI: 10.1002/dvdy.24537
• Languages: English
• ISSNs: 1058-8388

Abstract

Abstract : Background: Mutations in IRF6, CHUK (IKKA), and RIPK4 can lead to a disease spectrum that includes cutaneous, limb, and craniofacial malformations. Loss of these alleles in the mouse leads to perinatal lethality and severe cutaneous, limb, and craniofacial defects also. Genetic rescue in the mouse has been shown for Ikka and Ripk4 .Results: Here, we show partial genetic rescue of Irf6 knockout embryos using the KRT14 promoter to drive Irf6 expression in the basal epithelium. In contrast to Irf6 knockout embryos, rescue embryos survive the immediate perinatal period. Macroscopic examination reveals rescue of skin adhesions between the axial and appendicular skeleton. Unexpectedly, KRT14‐driven Irf6 expression does not completely rescue orofacial clefting and adhesions between the palate and tongue, suggesting the importance of cell‐autonomous IRF6 expression in periderm. Like knockout embryos, Irf6 rescue embryos also have persistent esophageal adhesions, which likely contribute to postnatal demise.Conclusions: Together, these data suggest that targeted expression of IRF6 can significantly reduce disease severity, but that a minimum level of Irf6 in both periderm and basal epithelial cells is necessary for orofacial development. Therefore, homologous human and mouse phenotypes are observed for IRF6, IKKA, and RIPK4. In this work, we show that altering the expression level of IRF6 dramatically modified this phenotype in utero. Developmental Dynamics 246:670–681, 2017 . © 2017 Wiley Periodicals, Inc. Key Findings: 1‐Epithelial IRF6 expression delays lethality. 2‐Epithelial IRF6 expression does not completely rescue limb and skeletal defects. 3‐Epithelial IRF6 expression partially rescue oral adhesions. 4‐Palatal adhesions to lingual epithelium perturbs elevation/re‐orientation of the palatal shelves. 5‐GRHL3, rather than KRT6, marks functional periderm.