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Altered FGF Signaling Pathways Impair Cell Proliferation and Elevation of Palate Shelves.

Wu W, Gu S, Sun C, He W, Xie X, Li X, Ye W, Qin C, Chen Y, Xiao J, Liu C - PLoS ONE (2015)

Bottom Line: In our study, we found that when Fgf8 is ectopically expressed in the embryonic palatal mesenchyme, the elevation of palatal shelves is impaired and the posterior palatal shelves are enlarged, especially in the medial side.The palatal deformity results from the drastic increase of cell proliferation in posterior mesenchyme and decrease of cell proliferation in epithelium.Besides the altered Fgf7, Fgf10, Dlx5 and Shh expression pattern, the reduced Osr2 expression domain in the lateral mesenchyme also suggests an impaired mediolateral patterning of posterior palate.

View Article: PubMed Central - PubMed

Affiliation: Department of Stomatology, Shanghai Zhongshan Hospital, Shanghai, China; Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America.

ABSTRACT
In palatogenesis, palatal shelves are patterned along the mediolateral axis as well as the anteroposterior axis before the onset of palatal fusion. Fgf10 specifically expressed in lateral mesenchyme of palate maintains Shh transcription in lateral epithelium, while Fgf7 activated in medial mesenchyme by Dlx5, suppressed the expansion of Shh expression to medial epithelium. How FGF signaling pathways regulate the cell behaviors of developing palate remains elusive. In our study, we found that when Fgf8 is ectopically expressed in the embryonic palatal mesenchyme, the elevation of palatal shelves is impaired and the posterior palatal shelves are enlarged, especially in the medial side. The palatal deformity results from the drastic increase of cell proliferation in posterior mesenchyme and decrease of cell proliferation in epithelium. The expression of mesenchymal Fgf10 and epithelial Shh in the lateral palate, as well as the Dlx5 and Fgf7 transcription in the medial mesenchyme are all interrupted, indicating that the epithelial-mesenchymal interactions during palatogenesis are disrupted by the ectopic activation of mesenchymal Fgf8. Besides the altered Fgf7, Fgf10, Dlx5 and Shh expression pattern, the reduced Osr2 expression domain in the lateral mesenchyme also suggests an impaired mediolateral patterning of posterior palate. Moreover, the ectopic Fgf8 expression up-regulates pJak1 throughout the palatal mesenchyme and pErk in the medial mesenchyme, but down-regulates pJak2 in the epithelium, suggesting that during normal palatogenesis, the medial mesenchymal cell proliferation is stimulated by FGF/Erk pathway, while the epithelial cell proliferation is maintained through FGF/Jak2 pathway.

No MeSH data available.


Related in: MedlinePlus

The examination on cell proliferation ratio of the developing palatal shelves of Osr2-CreKI; Rosa26R-Fgf8 mouse embryos.(A-D) Cell proliferation test by BrdU labelling for the E13.5 Osr2-CreKI; Ros26R-Fgf8 palatal shelves. The BrdU labelled cells in the E13.5 WT medial (red circle in A) and lateral palatal mesenchyme (blue circle in A) were less than those in the Osr2-CreKI; Ros26R-Fgf8 medial (violet circle in B) and lateral mesenchyme (green circle in B). Opposing to the mesenchymal cell proliferation ratio, the number of BrdU positive cells in the E13.5 WT palatal epithelium (arrows in C) was more than that in the mutant palatal epithelium (arrows in D). (E, F) Statistics of the numbers of BrdU labelled cells in the E13.5 palatal shelves. The number of proliferating medial mesenchymal cells significantly raised from 48.455 (SD = 8.722, SE = 2.629) in WT to 64.667 (SD = 5.937, SE = 1.979) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01). Similarly, the proliferating cells in lateral mesenchyme raised greatly from 50.455 (SD = 6.758, SE = 1.983) in WT to 61.556 (SD = 4.362, SE = 1.454) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01) (E). The difference in cell proliferation ratio between the medial and lateral palatal mesenchyme had no significance in both WT and Osr2-CreKI; Rosa26R-Fgf8 mouse (E). Reversely, the amount of proliferating cells in palatal epithelium dropped drastically from 19.364 (SD = 2.942, SE = 0.887) in WT to 13.322 (SD = 3.114, SE = 1.038) in the Osr2-CreKI; Ros26R-Fgf8 mouse (P<0.01) (F). (C and D were the enlarged areas of the square boxes in A and B, respectively; Dashed lines in C and D delineated the boundary between mesenchyme and epithelium; SD, Standard Derivation; SE, Standard Error; Scale bar: 200um)
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pone.0136951.g003: The examination on cell proliferation ratio of the developing palatal shelves of Osr2-CreKI; Rosa26R-Fgf8 mouse embryos.(A-D) Cell proliferation test by BrdU labelling for the E13.5 Osr2-CreKI; Ros26R-Fgf8 palatal shelves. The BrdU labelled cells in the E13.5 WT medial (red circle in A) and lateral palatal mesenchyme (blue circle in A) were less than those in the Osr2-CreKI; Ros26R-Fgf8 medial (violet circle in B) and lateral mesenchyme (green circle in B). Opposing to the mesenchymal cell proliferation ratio, the number of BrdU positive cells in the E13.5 WT palatal epithelium (arrows in C) was more than that in the mutant palatal epithelium (arrows in D). (E, F) Statistics of the numbers of BrdU labelled cells in the E13.5 palatal shelves. The number of proliferating medial mesenchymal cells significantly raised from 48.455 (SD = 8.722, SE = 2.629) in WT to 64.667 (SD = 5.937, SE = 1.979) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01). Similarly, the proliferating cells in lateral mesenchyme raised greatly from 50.455 (SD = 6.758, SE = 1.983) in WT to 61.556 (SD = 4.362, SE = 1.454) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01) (E). The difference in cell proliferation ratio between the medial and lateral palatal mesenchyme had no significance in both WT and Osr2-CreKI; Rosa26R-Fgf8 mouse (E). Reversely, the amount of proliferating cells in palatal epithelium dropped drastically from 19.364 (SD = 2.942, SE = 0.887) in WT to 13.322 (SD = 3.114, SE = 1.038) in the Osr2-CreKI; Ros26R-Fgf8 mouse (P<0.01) (F). (C and D were the enlarged areas of the square boxes in A and B, respectively; Dashed lines in C and D delineated the boundary between mesenchyme and epithelium; SD, Standard Derivation; SE, Standard Error; Scale bar: 200um)

Mentions: To explore how the constitutively activated Fgf8 enlarged the posterior palatal shelves, we compared the cell proliferation by BrdU labelling test between wild type and Osr2-CreKI; Rosa26R-Fgf8 posterior palatal shelves. Compared with their wild type littermates, the amount of BrdU labelled cells of E13.5 Osr2-CreKI; Rosa26R-Fgf8 posterior palatal shelves increased significantly in both medial and lateral mesenchyme (Fig 3A, 3B and 3E), but decreased drastically in the epithelium (from 19.364 to 13.222; Fig 3C, 3D and 3F). The number of BrdU positive cells of the medial mesenchyme (64.667) was higher than that of the lateral mesenchyme (61.556) in the E13.5 Osr2-CreKI; Rosa26R-Fgf8 palatal shelves (Fig 3E). In contrast, the proliferating medial mesenchymal cells (48.455) were less than those of lateral side (50.455) in the wild type palatal shelves (Fig 3E). However, these differences had no statistical significance (Fig 3E). The BrdU-labelling examination indicated that the enlarged palatal shelves of Osr2-CreKI; Rosa26R-Fgf8 mice resulted from the increased mesenchymal cell proliferation stimulated by the mesenchyme derived FGF8. It also implied that the palatal mesenchyme derived FGF8 had an inhibitory effect on the cell proliferation of palatal epithelium.


Altered FGF Signaling Pathways Impair Cell Proliferation and Elevation of Palate Shelves.

Wu W, Gu S, Sun C, He W, Xie X, Li X, Ye W, Qin C, Chen Y, Xiao J, Liu C - PLoS ONE (2015)

The examination on cell proliferation ratio of the developing palatal shelves of Osr2-CreKI; Rosa26R-Fgf8 mouse embryos.(A-D) Cell proliferation test by BrdU labelling for the E13.5 Osr2-CreKI; Ros26R-Fgf8 palatal shelves. The BrdU labelled cells in the E13.5 WT medial (red circle in A) and lateral palatal mesenchyme (blue circle in A) were less than those in the Osr2-CreKI; Ros26R-Fgf8 medial (violet circle in B) and lateral mesenchyme (green circle in B). Opposing to the mesenchymal cell proliferation ratio, the number of BrdU positive cells in the E13.5 WT palatal epithelium (arrows in C) was more than that in the mutant palatal epithelium (arrows in D). (E, F) Statistics of the numbers of BrdU labelled cells in the E13.5 palatal shelves. The number of proliferating medial mesenchymal cells significantly raised from 48.455 (SD = 8.722, SE = 2.629) in WT to 64.667 (SD = 5.937, SE = 1.979) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01). Similarly, the proliferating cells in lateral mesenchyme raised greatly from 50.455 (SD = 6.758, SE = 1.983) in WT to 61.556 (SD = 4.362, SE = 1.454) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01) (E). The difference in cell proliferation ratio between the medial and lateral palatal mesenchyme had no significance in both WT and Osr2-CreKI; Rosa26R-Fgf8 mouse (E). Reversely, the amount of proliferating cells in palatal epithelium dropped drastically from 19.364 (SD = 2.942, SE = 0.887) in WT to 13.322 (SD = 3.114, SE = 1.038) in the Osr2-CreKI; Ros26R-Fgf8 mouse (P<0.01) (F). (C and D were the enlarged areas of the square boxes in A and B, respectively; Dashed lines in C and D delineated the boundary between mesenchyme and epithelium; SD, Standard Derivation; SE, Standard Error; Scale bar: 200um)
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Related In: Results  -  Collection

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Show All Figures
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pone.0136951.g003: The examination on cell proliferation ratio of the developing palatal shelves of Osr2-CreKI; Rosa26R-Fgf8 mouse embryos.(A-D) Cell proliferation test by BrdU labelling for the E13.5 Osr2-CreKI; Ros26R-Fgf8 palatal shelves. The BrdU labelled cells in the E13.5 WT medial (red circle in A) and lateral palatal mesenchyme (blue circle in A) were less than those in the Osr2-CreKI; Ros26R-Fgf8 medial (violet circle in B) and lateral mesenchyme (green circle in B). Opposing to the mesenchymal cell proliferation ratio, the number of BrdU positive cells in the E13.5 WT palatal epithelium (arrows in C) was more than that in the mutant palatal epithelium (arrows in D). (E, F) Statistics of the numbers of BrdU labelled cells in the E13.5 palatal shelves. The number of proliferating medial mesenchymal cells significantly raised from 48.455 (SD = 8.722, SE = 2.629) in WT to 64.667 (SD = 5.937, SE = 1.979) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01). Similarly, the proliferating cells in lateral mesenchyme raised greatly from 50.455 (SD = 6.758, SE = 1.983) in WT to 61.556 (SD = 4.362, SE = 1.454) in the Osr2-CreKI; Rosa26R-Fgf8 mouse (P<0.01) (E). The difference in cell proliferation ratio between the medial and lateral palatal mesenchyme had no significance in both WT and Osr2-CreKI; Rosa26R-Fgf8 mouse (E). Reversely, the amount of proliferating cells in palatal epithelium dropped drastically from 19.364 (SD = 2.942, SE = 0.887) in WT to 13.322 (SD = 3.114, SE = 1.038) in the Osr2-CreKI; Ros26R-Fgf8 mouse (P<0.01) (F). (C and D were the enlarged areas of the square boxes in A and B, respectively; Dashed lines in C and D delineated the boundary between mesenchyme and epithelium; SD, Standard Derivation; SE, Standard Error; Scale bar: 200um)
Mentions: To explore how the constitutively activated Fgf8 enlarged the posterior palatal shelves, we compared the cell proliferation by BrdU labelling test between wild type and Osr2-CreKI; Rosa26R-Fgf8 posterior palatal shelves. Compared with their wild type littermates, the amount of BrdU labelled cells of E13.5 Osr2-CreKI; Rosa26R-Fgf8 posterior palatal shelves increased significantly in both medial and lateral mesenchyme (Fig 3A, 3B and 3E), but decreased drastically in the epithelium (from 19.364 to 13.222; Fig 3C, 3D and 3F). The number of BrdU positive cells of the medial mesenchyme (64.667) was higher than that of the lateral mesenchyme (61.556) in the E13.5 Osr2-CreKI; Rosa26R-Fgf8 palatal shelves (Fig 3E). In contrast, the proliferating medial mesenchymal cells (48.455) were less than those of lateral side (50.455) in the wild type palatal shelves (Fig 3E). However, these differences had no statistical significance (Fig 3E). The BrdU-labelling examination indicated that the enlarged palatal shelves of Osr2-CreKI; Rosa26R-Fgf8 mice resulted from the increased mesenchymal cell proliferation stimulated by the mesenchyme derived FGF8. It also implied that the palatal mesenchyme derived FGF8 had an inhibitory effect on the cell proliferation of palatal epithelium.

Bottom Line: In our study, we found that when Fgf8 is ectopically expressed in the embryonic palatal mesenchyme, the elevation of palatal shelves is impaired and the posterior palatal shelves are enlarged, especially in the medial side.The palatal deformity results from the drastic increase of cell proliferation in posterior mesenchyme and decrease of cell proliferation in epithelium.Besides the altered Fgf7, Fgf10, Dlx5 and Shh expression pattern, the reduced Osr2 expression domain in the lateral mesenchyme also suggests an impaired mediolateral patterning of posterior palate.

View Article: PubMed Central - PubMed

Affiliation: Department of Stomatology, Shanghai Zhongshan Hospital, Shanghai, China; Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America.

ABSTRACT
In palatogenesis, palatal shelves are patterned along the mediolateral axis as well as the anteroposterior axis before the onset of palatal fusion. Fgf10 specifically expressed in lateral mesenchyme of palate maintains Shh transcription in lateral epithelium, while Fgf7 activated in medial mesenchyme by Dlx5, suppressed the expansion of Shh expression to medial epithelium. How FGF signaling pathways regulate the cell behaviors of developing palate remains elusive. In our study, we found that when Fgf8 is ectopically expressed in the embryonic palatal mesenchyme, the elevation of palatal shelves is impaired and the posterior palatal shelves are enlarged, especially in the medial side. The palatal deformity results from the drastic increase of cell proliferation in posterior mesenchyme and decrease of cell proliferation in epithelium. The expression of mesenchymal Fgf10 and epithelial Shh in the lateral palate, as well as the Dlx5 and Fgf7 transcription in the medial mesenchyme are all interrupted, indicating that the epithelial-mesenchymal interactions during palatogenesis are disrupted by the ectopic activation of mesenchymal Fgf8. Besides the altered Fgf7, Fgf10, Dlx5 and Shh expression pattern, the reduced Osr2 expression domain in the lateral mesenchyme also suggests an impaired mediolateral patterning of posterior palate. Moreover, the ectopic Fgf8 expression up-regulates pJak1 throughout the palatal mesenchyme and pErk in the medial mesenchyme, but down-regulates pJak2 in the epithelium, suggesting that during normal palatogenesis, the medial mesenchymal cell proliferation is stimulated by FGF/Erk pathway, while the epithelial cell proliferation is maintained through FGF/Jak2 pathway.

No MeSH data available.


Related in: MedlinePlus