title: IRF6 is the mediator of TGFβ3 during regulation of the epithelial mesenchymal transition and palatal fusion.
abstract: Mutation in interferon regulatory factor 6 (IRF6) is known to cause syndromic and non-syndromic cleft lip/palate in human. In this study, we investigated the molecular mechanisms related to IRF6 during palatal fusion using palatal shelves organ culture. The results showed that ablation of Irf6 resulted in a delay in TGFβ3-regulated palatal fusion. Ectopic expression of IRF6 was able to promote palatal fusion and rescue shTgfβ3-induced fusion defect. These findings indicate that IRF6 is involved in TGFβ3-mediated palatal fusion. Molecular analysis revealed that ectopic expression of IRF6 increased the expression of SNAI2, an epithelial mesenchymal transition (EMT) regulator, and diminished the expression of various epithelial markers, such as E-cadherin, Plakophilin and ZO-1. In addition, knockdown of Irf6 expression decreased SNAI2 expression, and restored the expression of ZO-1 and Plakophilin that were diminished by TGFβ3. Blocking of Snai2 expression delayed palatal fusion and abolished the IRF6 rescuing effect associated with shTgfβ3-induced fusion defect. These findings indicate that TGFβ3 increases IRF6 expression and subsequently regulates SNAI2 expression, and IRF6 appears to regulate EMT during palatal fusion via SNAI2. Taken together, this study demonstrates that IRF6 is a mediator of TGFβ3, which regulates EMT and fusion process during the embryonic palate development.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, 11221, Taiwan.
authors.forename: Chen-Yeh
authors.initials: CY
authors.lastname: Ke
authors.affiliation: Department of Plastic and Reconstructive Surgery, and Craniofacial Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, 333, Taiwan.
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Xiao
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, 11221, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Plastic and Reconstructive Surgery, and Craniofacial Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, 333, Taiwan.
authors.forename: Lun-Jou
authors.initials: LJ
authors.lastname: Lo
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, 11221, Taiwan.
authors.forename: Fen-Hwa
authors.initials: FH
authors.lastname: Wong
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D009924:Organ Culture Techniques; D010159:Palate / Q000254:growth & development / Q000378:metabolism*; D051191:Plakophilins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors; C495336:Pkp1 protein, mouse; D051191:Plakophilins; D034741:RNA, Small Interfering; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C569043:Tjp1 protein, mouse; D014157:Transcription Factors; D053782:Transforming Growth Factor beta3; D051879:Twist-Related Protein 1; D062826:Zonula Occludens-1 Protein