Cell-Autonomous and Non-Cell-Autonomous Roles for Irf6 during Development of the Tongue

Abstract

Interferon regulatory factor 6 (IRF6) encodes a highly conserved helix-turn-helix DNA binding protein and is a member of the interferon regulatory family of DNA transcription factors. Mutations in IRF6 lead to isolated and syndromic forms of cleft lip and palate, most notably Van der Woude syndrome (VWS) and Popliteal Ptyerigium Syndrome (PPS). Mice lacking both copies of Irf6 have severe limb, skin, palatal and esophageal abnormalities, due to significantly altered and delayed epithelial development. However, a recent report showed that MCS9.7, an enhancer near Irf6, is active in the tongue, suggesting that Irf6 may also be expressed in the tongue. Indeed, we detected Irf6 staining in the mesoderm-derived muscle during development of the tongue. Dual labeling experiments demonstrated that Irf6 was expressed only in the Myf5+ cell lineage, which originates from the segmental paraxial mesoderm and gives rise to the muscles of the tongue. Fate mapping of the segmental paraxial mesoderm cells revealed a cell-autonomous Irf6 function with reduced and poorly organized Myf5+ cell lineage in the tongue. Molecular analyses showed that the Irf6−/− embryos had aberrant cytoskeletal formation of the segmental paraxial mesoderm in the tongue. Fate mapping of the cranial neural crest cells revealed non-cell-autonomous Irf6 function with the loss of the inter-molar eminence. Loss of Irf6 function altered Bmp2, Bmp4, Shh, and Fgf10 signaling suggesting that these genes are involved in Irf6 signaling. Based on these data, Irf6 plays important cell-autonomous and non-cell-autonomous roles in muscular differentiation and cytoskeletal formation in the tongue.

Syngnathia and obstructive apnea in a case of popliteal pterygium syndrome

“…PPS is part of a spectrum of disorders associated with mutations in IRF6 , which plays an important role in keratinocyte and lingual development [11,6]. …”

Haplotype‐based gene–gene interaction of bone morphogenetic protein 4 and interferon regulatory factor 6 in the etiology of non‐syndromic cleft lip with or without cleft palate in a Chilean population

“…This is the case of Irf6 − / − mice showing a decrease in the proliferation of the cells forming the tongue as a result of cytoskeletal defects. Those cells also had diminished expression of several genes, such as Bmp4 . Therefore, the gene–gene interaction described here has no precedence in the development of palate and/or upper lip tissues to date.…”

Regional regulation of Filiform tongue papillae development by Ikkα/Irf6

“…Irf6 mutant ( Irf6 R84C/R84C ) mice are known to show evagination of incisor epithelium, palatal clefting, and fusion of oral epithelium, which are also seen in Ikkα mutant mice (Richardson et al, , , ; Ingraham et al, ; Thomason et al, ; Blackburn et al, 2012; Ferretti et al, ; Iwata et al, ). Irf6 has additionally been shown to be involved in tongue muscle development (Goudy et al, ). Irf6 was strongly expressed in tongue epithelium including the non‐dorsum part of tongue (Fig.…”