title: Fibroblast growth factor 9 (FGF9)-pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor β (TGFβ) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis.
abstract: Cleft palate represents one of the most common congenital birth defects. Transforming growth factor β (TGFβ) signaling plays crucial functions in regulating craniofacial development, and loss of TGFβ receptor type II in cranial neural crest cells leads to craniofacial malformations, including cleft palate in mice (Tgfbr2(fl/fl);Wnt1-Cre mice). Here we have identified candidate target genes of TGFβ signaling during palatal formation. These target genes were selected based on combining results from gene expression profiles of embryonic day 14.5 palates from Tgfbr2(fl/fl);Wnt1-Cre mice and previously identified cleft palate phenotypes in genetically engineered mouse models. We found that fibroblast growth factor 9 (Fgf9) and transcription factor pituitary homeobox 2 (Pitx2) expressions are significantly down-regulated in the palate of Tgfbr2(fl/fl);Wnt1-Cre mice, and Fgf9 and Pitx2 loss of function mutations result in cleft palate in mice. Pitx2 expression is down-regulated by siRNA knockdown of Fgf9, suggesting that Fgf9 is upstream of Pitx2. We detected decreased expression of both cyclins D1 and D3 in the palates of Tgfbr2(fl/fl);Wnt1-Cre mice, consistent with the defect in cell proliferation. Significantly, exogenous FGF9 restores expression of cyclins D1 and D3 in a Pitx2-dependent manner and rescues the cell proliferation defect in the palatal mesenchyme of Tgfbr2(fl/fl);Wnt1-Cre mice. Our study indicates that a TGFβ-FGF9-PITX2 signaling cascade regulates cranial neural crest cell proliferation during palate formation.
authors: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California 90033, USA.
authors: Jun-ichi
authors: J
authors: Iwata
authors: Lily
authors: L
authors: Tung
authors: Mark
authors: M
authors: Urata
authors: Joseph G
authors: JG
authors: Hacia
authors: Richard
authors: R
authors: Pelikan
authors: Akiko
authors: A
authors: Suzuki
authors: Liza
authors: L
authors: Ramenzoni
authors: Obaid
authors: O
authors: Chaudhry
authors: Carolina
authors: C
authors: Parada
authors: Pedro A
authors: PA
authors: Sanchez-Lara
authors: Yang
authors: Y
authors: Chai
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000196:embryology; D010159:Palate / Q000196:embryology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000097577:Homeobox Protein PITX2
chemical_list: D051525:Fibroblast Growth Factor 9; D018398:Homeodomain Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000097577:Homeobox Protein PITX2; C496460:Fgf9 protein, mouse