title: Induction of palate epithelial mesenchymal transition by transforming growth factor β3 signaling.
abstract: Transforming growth factor (TGFβ)3 is essential for palate development, particularly during the late phase of palatogenesis when the disintegration of the palatal medial edge seam (MES) occurs resulting in mesenchymal confluence. The MES is composed of medial-edge epithelium (MEE) of opposite palatal shelves; its complete disintegration is essential for mediating correct craniofacial morphogenesis. This phenomenon is initiated by TGFβ3 upon adherence of opposing palatal shelves, and subsequently epithelial-mesenchymal transition (EMT) instigates the loss of E-Cadherin, causing the MES to break into small epithelial islands forming confluent palatal mesenchyme; however, apoptosis and cell migration or in combination of all are other established mechanisms of seam disintegration. To investigate the molecular mechanisms that cause this E-Cadherin loss, we isolated and cultured murine embryonic primary MES cells from adhered palates and employed several biological approaches to explore the mechanism by which TGFβ3 facilitates palatal seam disintegration. Here, we demonstrate that TGFβ3 signals by activating both Smad-dependent and Smad-independent pathways. However, activation of the two most common EMT related transcription factors, Snail and SIP, was facilitated by Smad-independent pathways, contrary to the commonly accepted Smad-dependent pathway. Finally, we provide the first evidence that TGFβ3-activated Snail and SIP1, combined with Smad4, bind to the E-Cadherin promoter to repress its transcription in response to TGFβ3 signaling. These results suggest that TGFβ3 uses multiple pathways to activate Snail and SIP1 and these transcription factors repress the cell-cell adhesion protein, E-Cadherin, to induce palatal epithelial seam EMT. Manipulation and intervention of the pathways stimulated by TGFβ3 during palate development may have a significant therapeutic potential.
authors: Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68512, USA.
authors: Azadeh
authors: A
authors: Jalali
authors: Xiujuan
authors: X
authors: Zhu
authors: ChangChih
authors: C
authors: Liu
authors: Ali
authors: A
authors: Nawshad
mesh_terms: D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D004848:Epithelium / Q000378:metabolism / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000502:physiology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010159:Palate / Q000166:cytology / Q000502:physiology*; D011247:Pregnancy; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C509045:Tgfb3 protein, mouse; D053782:Transforming Growth Factor beta3; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2