Regulation of Epithelial-Mesenchymal Transition in Palatal Fusion

Wang, Yu; Ruest, L. Bruno; Svoboda, Kathy K.H.

doi:10.3181/0812-mr-365

Cited by 46 publications

(41 citation statements)

References 108 publications

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“…Apoptotic and migratory processes are well-known important mechanisms to explain MES degeneration (Carette and Ferguson 1992;Mori et al 1994;Taniguchi et al 1995;Cuervo and Covarrubias 2004;Vaziri Sani et al 2005). However, another major mechanism that has been strongly proposed to explain MES degeneration is the EMT (Griffith and Hay, 1992;Shuler et al 1991Shuler et al , 1992Kaartinen et al 1997;Nieto 2002;Nawshad et al 2004;Jin and Ding 2006;Yu et al 2009). We identified the molecular interaction between miR200b and Tgf-b-mediated Smad2 and Snail by reporter assay and overexpression of miR-200b.…”

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

confidence: 97%

“…Snail expression is activated by Tgf-b signaling (MartinezAlvarez et al 2004;Yu et al 2009), and Snail can then directly repress expression of E-cadherin (Carver et al 2001;Beltran et al 2008). Snail family genes are essential for correct palate formation and mutant mice of Snail family genes have cleft palate due to reduced apoptosis during palatogenesis (Murray et al 2007).…”

Section: Introductionmentioning

confidence: 98%

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

confidence: 97%

Section: Introductionmentioning

confidence: 98%

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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“…For all these mechanisms to occur properly in both mice and humans, the presence of transforming growth factor-␤ 3 (TGF-␤ 3 ) is crucial [Kaartinen et al, 1995;Proetzel et al, 1995;Lidral et al, 1998;Mitchell et al, 2001]. Its gene, together with those of TGF-␤ 1 and TGF-␤ 2 , is expressed in the mouse palate from E13 to E15 [Fitzpatrick et al, 1990;Pelton et al, 1990], where it triggers a phosphorylation cascade involving both SMAD-dependent and independent pathways [reviewed in Yu et al, 2009]. Experiments using Tgf-␤ 3 null mutant ( Tgf-␤ 3 -/-) mice demonstrated that SMAD2, but not SMAD3, is phosphorylated upon activation of TGF-␤ receptors and mediates most of the mechanisms causing palatal fusion [Cui et al, 2003[Cui et al, , 2005Shiomi et al, 2006].…”

mentioning

confidence: 99%

Occurrence of Cleft-Palate and Alteration of Tgf-β3 Expression and the Mechanisms Leading to Palatal Fusion in Mice following Dietary Folic-Acid Deficiency

Maldonado

Murillo

Barrio

et al. 2011

Cells Tissues Organs

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Folic acid (FA) is essential for numerous bodily functions. Its decrease during pregnancy has been associated with an increased risk of congenital malformations in the progeny. The relationship between FA deficiency and the appearance of cleft palate (CP) is controversial, and little information exists on a possible effect of FA on palate development. We investigated the effect of a 2–8 weeks’ induced FA deficiency in female mice on the development of CP in their progeny as well as the mechanisms leading to palatal fusion, i.e. cell proliferation, cell death, and palatal-shelf adhesion and fusion. We showed that an 8 weeks’ maternal FA deficiency caused complete CP in the fetuses although a 2 weeks’ maternal FA deficiency was enough to alter all the mechanisms analyzed. Since transforming growth factor-β₃ (TGF-β₃) is crucial for palatal fusion and since most of the mechanisms impaired by FA deficiency were also observed in the palates of Tgf-β₃null mutant mice, we investigated the presence of TGF-β₃ mRNA, its protein and phospho-SMAD2 in FA-deficient (FAD) mouse palates. Our results evidenced a large reduction in Tgf-β₃ expression in palates of embryos of dams fed an FAD diet for 8 weeks; Tgf-β₃ expression was less reduced in palates of embryos of dams fed an FAD diet for 2 weeks. Addition of TGF-β₃ to palatal-shelf cultures of embryos of dams fed an FAD diet for 2 weeks normalized all the altered mechanisms. Thus, an insufficient folate status may be a risk factor for the development of CP in mice, and exogenous TGF-β₃ compensates this deficit in vitro.

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“…Then the complex translocates into the nucleus and binds the target gene to regulate gene expression in a cell type-specific and ligand dose-dependent manner. 18 TGF-A signaling pathway is correlated to the disappearance of MEE 10,19 and the proliferation of palatal mesenchymal cells. 20 To investigate the role of TGF-A signal pathway in palatogenesis, in vivo targeted mutations of individual gene were generated.…”

Section: Transforming Growth Factor a Familymentioning

confidence: 99%

“…The phenotypes range from early embryonic lethality to subtle phenotypes in adult mice. Specifically, some FGFs (FGF4, 8,9,10,15, and 18) knockout mice die during pregnancy or postnatal day, 44Y50 whereas others display different phenotypes. A strong association between FGFs and palatal anatomy suggested the role they played in palatal development.…”

Section: Fibroblast Growth Factormentioning

confidence: 99%

Targeted Mutations of Genes Reveal Important Roles in Palatal Development in Mice

Ma¹,

Shi²,

Zheng³

2015

Annals of Plastic Surgery

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The process of palatal development is regulated by growth factors, extracellular matrix (ECM) protein, and cell adhesion molecules, of which disturbance may result in cleft palate. Knockout mice are important animal models for studying the role of genes during palatal development. Therefore, in this review, we will describe genes knockout in mice to reveal the biological mechanisms of these genes in the formation of the cleft palate.

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Regulation of Epithelial-Mesenchymal Transition in Palatal Fusion

Cited by 46 publications

References 108 publications

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

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

Occurrence of Cleft-Palate and Alteration of <i>Tgf-</i>β<sub><i>3</i></sub> Expression and the Mechanisms Leading to Palatal Fusion in Mice following Dietary Folic-Acid Deficiency

Targeted Mutations of Genes Reveal Important Roles in Palatal Development in Mice

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