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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.

SUBMITTER: Ke CY

PROVIDER: S-EPMC4523936 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus.To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays.Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools.We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion.Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.The previous version was incorrect. New authors Ali Nawshad, Hasan Otu, Janki Sharma, and Elizabeth Sheldon have been included in this version; the funding and acknowledgement sections have been updated accordingly; the article title, some text, and one supplementary data file have been edited; and the corresponding author has been changed. The original corresponding author regrets these earlier errors.

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IRF6 is the mediator of TGFβ3 during regulation of the epithelial mesenchymal transition and palatal fusion.

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