Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
Dev Biol. 2011 Feb 15;350(2):511-9. doi: 10.1016/j.ydbio.2010.12.021. Epub 2010 Dec 23.
The canonical Wnt/β-catenin signaling plays essential role in development and diseases. Previous studies have implicated the canonical Wnt/β-catenin signaling in the regulation of normal palate development, but functional Wnt/β-catenin signaling and its tissue-specific activities remain to be accurately elucidated. In this study, we show that functional Wnt/β-catenin signaling operates primarily in the palate epithelium, particularly in the medial edge epithelium (MEE) of the developing mouse palatal shelves, consistent with the expression patterns of β-catenin and several Wnt ligands and receptors. Epithelial specific inactivation of β-catenin by the K14-Cre transgenic allele abolishes the canonical Wnt signaling activity in the palatal epithelium and leads to an abnormal persistence of the medial edge seam (MES), ultimately causing a cleft palate formation, a phenotype resembling that in Tgfβ3 mutant mice. Consistent with this phenotype is the down-regulation of Tgfβ3 and suppression of apoptosis in the MEE of the β-catenin mutant palatal shelves. Application of exogenous Tgfβ3 to the mutant palatal shelves in organ culture rescues the midline seam phenotype. On the other hand, expression of stabilized β-catenin in the palatal epithelium also disrupts normal palatogenesis by activating ectopic Tgfβ3 expression in the palatal epithelium and causing an aberrant fusion between the palate shelf and mandible in addition to severely deformed palatal shelves. Collectively, our results demonstrate an essential role for Wnt/β-catenin signaling in the epithelial component at the step of palate fusion during palate development by controlling the expression of Tgfβ3 in the MEE.
经典的 Wnt/β-连环蛋白信号通路在发育和疾病中起着重要作用。先前的研究表明，经典的 Wnt/β-连环蛋白信号通路参与了正常腭发育的调控，但功能性 Wnt/β-连环蛋白信号通路及其组织特异性活性仍有待准确阐明。在这项研究中，我们表明功能性 Wnt/β-连环蛋白信号通路主要在腭上皮中起作用，特别是在发育中的小鼠腭突的内侧缘上皮（MEE）中，这与β-连环蛋白和几种 Wnt 配体和受体的表达模式一致。通过 K14-Cre 转基因等位基因对β-连环蛋白的上皮特异性失活，消除了腭上皮中的经典 Wnt 信号活性，并导致内侧缘缝（MES）异常持续存在，最终导致腭裂形成，表型类似于 Tgfβ3 突变小鼠。与这种表型一致的是，β-连环蛋白突变的腭突 MEE 中 Tgfβ3 的下调和细胞凋亡的抑制。外源性 Tgfβ3 在器官培养中应用于突变的腭突可以挽救中线缝表型。另一方面，稳定的β-连环蛋白在腭上皮中的表达也通过激活腭上皮中的异位 Tgfβ3 表达以及除了严重变形的腭突之外，还导致腭突和下颌骨之间的异常融合，从而破坏正常的腭发育。总之，我们的结果表明，Wnt/β-连环蛋白信号通路通过控制 MEE 中 Tgfβ3 的表达，在腭融合阶段的腭发育中对上皮成分起着重要作用。
