Inhibition of SMAD2 expression prevents murine palatal fusion

Shiomi, Nobuyuki; Cui, Xiao Mei; Yamamoto, Tadashi; Saito, Takashi; Shuler, Charles F.

doi:10.1002/dvdy.20819

Cited by 20 publications

(27 citation statements)

References 37 publications

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“…This portrays a major discovery in this system, because LEF1 has most commonly been described as being activated by ␤-catenin, as demonstrated in traditional Wnt signaling. These data are justified by previous findings that Wnt-knockout mice show no evidence of palatal clefting, whereas LEF1- (Galceran et al, 1999) and TGF␤3- (Taya et al, 1999) Journal of Cell Science 120 (9) findings of Smad2 knockdown by small interfering RNA (siRNA) in preventing palatal confluence (Shiomi et al, 2006) further support these data. Why ␤-catenin remains in the cytoplasm during palatal EMT remains to be determined.…”

Section: Discussionsupporting

confidence: 57%

TGFβ3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex

Nawshad

Medici

Liu

et al. 2007

Journal of Cell Science

136

159

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Dissociation of medial-edge epithelium (MEE) during palate development is essential for mediating correct craniofacial morphogenesis. This phenomenon is initiated by TGFβ3 upon adherence of opposing palatal shelves, because loss of E-cadherin causes the MEE seam to break into small epithelial islands. To investigate the molecular mechanisms that cause this E-cadherin loss, we isolated and cultured murine embryonic primary MEE cells from adhered or non-adhered palates. Here, we provide the first evidence that lymphoid enhancer factor 1 (LEF1), when functionally activated by phosphorylated Smad2 (Smad2-P) and Smad4 (rather than β-catenin), binds with the promoter of the E-cadherin gene to repress its transcription in response to TGFβ3 signaling. Furthermore, we found that TGFβ3 signaling stimulates epithelial-mesenchymal transformation (EMT) and cell migration in these cells. LEF1 and Smad4 were found to be necessary for up-regulation of the mesenchymal markers vimentin and fibronectin, independently of β-catenin. We proved that TGFβ3 signaling induces EMT in MEE cells by forming activated transcription complexes of Smad2-P, Smad4 and LEF1 that directly inhibit E-cadherin gene expression.

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Section: Discussionsupporting

confidence: 57%

TGFβ3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex

Nawshad

Medici

Liu

et al. 2007

Journal of Cell Science

136

159

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“…How exactly these three ligands differ in downstream signaling potential remains to be defined, as they all signal through Smad proteins. Whereas they all have the potential to use both Smad2 and Smad3, recent evidence has shown that TGF-␤3 primarily uses Smad2 as its R-Smad protein during EMT (Nawshad and Hay, 2003;Shiomi et al, 2006). Therefore, it is tempting to hypothesize that TGF-␤1 and TGF-␤2 primarily use Smad3 as their R-Smad during EMT.…”

Section: Discussionmentioning

confidence: 99%

Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin–T-Cell Factor-4-dependent Expression of Transforming Growth Factor-β3

Medici

Hay

Olsen

2008

MBoC

449

371

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Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of ␤-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-␤3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-␤3 signaling increases LEF-1 gene expression causing formation of ␤-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-␤1 or TGF-␤2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-␤1-and TGF-␤2-induced EMT were found to be TGF-␤3 dependent, establishing essential roles for multiple TGF-␤ isoforms. Finally, we determined that ␤-catenin-LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-␤ and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype.

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“…When Smad2 is inhibited during mouse palate development, the MES is not degenerated (Shiomi et al 2006). Snail is associated with cell survival and cell movement during palatogenesis (Carver et al 2001;Nieto 2002;Barrallo-Gimeno and Nieto 2005) and is regulated by Tgf-b-mediated Smad2 (Martinez-Alvarez et al 2004).…”

Section: Mir-200b Modulates E-cadherin and Tgf-b-mediated Smad2 And Smentioning

confidence: 99%

MiR-200b is involved in Tgf-β signaling to regulate mammalian palate development

Shin

Lee

Cho

et al. 2011

Histochem Cell Biol

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Various cellular and molecular events are involved in palatogenesis, including apoptosis, epithelial-mesenchymal transition (EMT), cell proliferation, and cell migration. Smad2 and Snail, which are well-known key mediators of the transforming growth factor beta (Tgf-β) pathway, play a crucial role in the regulation of palate development. Regulatory effects of microRNA 200b (miR-200b) on Smad2 and Snail in palatogenesis have not yet been elucidated. The aim of this study is to determine the relationship between palate development regulators miR-200b and Tgf-β-mediated genes. Expression of miR-200b, E-cadherin, Smad2, and Snail was detected in the mesenchyme of the mouse palate, while miR-200b was expressed in the medial edge epithelium (MEE) and palatal mesenchyme. After the contact of palatal shelves, miR-200b was no longer expressed in the mesenchyme around the fusion region. The binding activity of miR-200b to both Smad2 and Snail was examined using a luciferase assay. MiR-200b directly targeted Smad2 and Snail at both cellular and molecular levels. The function of miR-200b was determined by overexpression via a lentiviral vector in the palatal shelves. Ectopic expression of miR-200b resulted in suppression of these Tgf-β-mediated regulators and changes of apoptosis and cell proliferation in the palatal fusion region. These results suggest that miR-200b plays a crucial role in regulating the Smad2, Snail, and in apoptosis during palatogenesis by acting as a direct non-coding, influencing factor. Furthermore, the molecular interactions between miR-200b and Tgf-β signaling are important for proper palatogenesis and especially for palate fusion. Elucidating the mechanism of palatogenesis may aid the design of effective gene-based therapies for the treatment of congenital cleft palate.

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Inhibition of SMAD2 expression prevents murine palatal fusion

Cited by 20 publications

References 37 publications

TGFβ3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex

TGFβ3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex

Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin–T-Cell Factor-4-dependent Expression of Transforming Growth Factor-β3

MiR-200b is involved in Tgf-β signaling to regulate mammalian palate development

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