Hu Lihua, Liu Jingpeng, Li Zhi, Ozturk Ferhat, Gurumurthy Channabasavaiah, Romano Rose-Anne, Sinha Satrajit, Nawshad Ali
Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska; Department of Orthodontics, Shandong Provincial Key Laboratory of Oral Biomedicine, School of Stomatology, Shandong University, Jinan, China.
J Cell Physiol. 2015 Jun;230(6):1212-25. doi: 10.1002/jcp.24856.
The periderm is a flat layer of epithelium created during embryonic development. During palatogenesis, the periderm forms a protective layer against premature adhesion of the oral epithelia, including the palate. However, the periderm must be removed in order for the medial edge epithelia (MEE) to properly adhere and form a palatal seam. Improper periderm removal results in a cleft palate. Although the timing of transforming growth factor β3 (TGFβ3) expression in the MEE coincides with periderm degeneration, its role in periderm desquamation is not known. Interestingly, murine models of knockout (-/-) TGFβ3, interferon regulatory factor 6 (IRF6) (-/-), and truncated p63 (ΔNp63) (-/-) are born with palatal clefts because of failure of the palatal shelves to adhere, suggesting that these genes regulate palatal epithelial differentiation. However, despite having similar phenotypes in null mouse models, no studies have analyzed the possible association between the TGFβ3 signaling cascade and the IRF6/ΔNp63 genes during palate development. Recent studies indicate that regulation of ΔNp63, which depends on IRF6, facilitates epithelial differentiation. We performed biochemical analysis, gene activity and protein expression assays with palatal sections of TGFβ3 (-/-), ΔNp63 (-/-), and wild-type (WT) embryos, and primary MEE cells from WT palates to analyze the association between TGFβ3 and IRF6/ΔNp63. Our results suggest that periderm degeneration depends on functional TGFβ3 signaling to repress ΔNp63, thereby coordinating periderm desquamation. Cleft palate occurs in TGFβ3 (-/-) because of inadequate periderm removal that impedes palatal seam formation, while cleft palate occurs in ΔNp63 (-/-) palates because of premature fusion.
周皮是胚胎发育过程中形成的一层扁平上皮。在腭发育过程中，周皮形成一层保护层，防止包括腭在内的口腔上皮过早粘连。然而，为了使内侧边缘上皮（MEE）正常粘连并形成腭缝，周皮必须被去除。周皮去除不当会导致腭裂。尽管MEE中转化生长因子β3（TGFβ3）表达的时间与周皮退化一致，但其在周皮脱屑中的作用尚不清楚。有趣的是，敲除（-/-）TGFβ3、干扰素调节因子6（IRF6）（-/-）和截短型p63（ΔNp63）（-/-）的小鼠模型出生时伴有腭裂，原因是腭突未能粘连，这表明这些基因调节腭上皮分化。然而，尽管在基因敲除小鼠模型中具有相似的表型，但尚无研究分析腭发育过程中TGFβ3信号级联与IRF6/ΔNp63基因之间可能的关联。最近的研究表明，依赖于IRF6的ΔNp63的调节促进上皮分化。我们对TGFβ3（-/-）、ΔNp63（-/-）和野生型（WT）胚胎的腭部切片以及来自WT腭的原代MEE细胞进行了生化分析、基因活性和蛋白质表达测定，以分析TGFβ3与IRF6/ΔNp63之间的关联。我们的结果表明，周皮退化依赖于功能性TGFβ3信号来抑制ΔNp63，从而协调周皮脱屑。TGFβ3（-/-）中出现腭裂是因为周皮去除不足，阻碍了腭缝形成，而ΔNp63（-/-）腭中出现腭裂是因为过早融合。
