Altered FGF Signaling Pathways Impair Cell Proliferation and Elevation of Palate Shelves.
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.
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.
Weijie
W
Wu
Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America.
Shuping
S
Gu
Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America.
Cheng
C
Sun
Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America; Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Zunyi Medical University, Zunyi, China.
Wei
W
He
Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Sciences Center, Dallas, Texas, United States of America; Department of Endodontics, Institute of Hard Tissue Development and Regeneration, the 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
Xiaohua
X
Xie
Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Xihai
X
Li
Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America.
Wenduo
W
Ye
Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Sciences Center, Dallas, Texas, United States of America.
Chunlin
C
Qin
Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America.
Yiping
Y
Chen
Department of Oral Biology, College of Stomatology, Dalian Medical University, Dalian, China.
Jing
J
Xiao
Department of Cell & Molecular Biology, Sciences and Engineering School, Tulane University, New Orleans, Louisiana, United States of America; Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Sciences Center, Dallas, Texas, United States of America; Department of Oral Biology, College of Stomatology, Dalian Medical University, Dalian, China.
Chao
C
Liu
D000818:Animals; D049109:Cell Proliferation; D002972:Cleft Palate / Q000235:genetics*; D051524:Fibroblast Growth Factor 8 / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics; D051379:Mice; D010159:Palate / Q000002:abnormalities* / Q000166:cytology / Q000196:embryology*; D022661:RNA, Untranslated / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
C496457:Fgf8 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D053823:Hedgehog Proteins; C438618:Osr2 protein, mouse; D022661:RNA, Untranslated; C465570:Shh protein, mouse; D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8