IRF6 is the mediator of TGFβ3 during regulation of the epithelial mesenchymal transition and palatal fusion.
IRF6 is the mediator of TGFβ3 during regulation of the epithelial mesenchymal transition and palatal fusion.
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DOI：
10.1038/srep12791
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发表时间：
2015-08-04
影响因子：
4.6
通讯作者：
Wong FH
中科院分区：
文献类型：
--
作者：
Ke CY;Xiao WL;Chen CM;Lo LJ;Wong FH
干扰素调节因子 6 (IRF6) 的突变已知会导致人类综合征性和非综合征性唇裂/腭裂。在本研究中，我们利用腭架器官培养研究了腭融合过程中与 IRF6 相关的分子机制。结果表明，Irf6 的消融导致 TGFβ3 调节的腭融合延迟。 IRF6 的异位表达能够促进腭融合并挽救 shTgfβ3 诱导的融合缺陷。这些发现表明 IRF6 参与 TGFβ3 介导的腭融合。分子分析显示，IRF6 的异位表达增加了 SNAI2（一种上皮间质转化 (EMT) 调节因子）的表达，并减少了各种上皮标志物的表达，如 E-钙粘蛋白、Plakophilin 和 ZO-1。此外，Irf6表达的敲除降低了SNAI2的表达，并恢复了被TGFβ3减少的ZO-1和Plakophilin的表达。阻断 Snai2 表达可延迟腭融合并消除与 shTgfβ3 诱导的融合缺陷相关的 IRF6 拯救作用。这些发现表明，TGFβ3 增加 IRF6 表达，随后调节 SNAI2 表达，并且 IRF6 似乎通过 SNAI2 调节腭融合过程中的 EMT。综上所述，这项研究表明 IRF6 是 TGFβ3 的介体，TGFβ3 调节胚胎上颚发育过程中的 EMT 和融合过程。
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.