title: Tak1, Smad4 and Trim33 redundantly mediate TGF-β3 signaling during palate development.
abstract: Transforming growth factor-beta3 (TGF-β3) plays a critical role in palatal epithelial cells by inducing palatal epithelial fusion, failure of which results in cleft palate, one of the most common birth defects in humans. Recent studies have shown that Smad-dependent and Smad-independent pathways work redundantly to transduce TGF-β3 signaling in palatal epithelial cells. However, detailed mechanisms by which this signaling is mediated still remain to be elucidated. Here we show that TGF-β activated kinase-1 (Tak1) and Smad4 interact genetically in palatal epithelial fusion. While simultaneous abrogation of both Tak1 and Smad4 in palatal epithelial cells resulted in characteristic defects in the anterior and posterior secondary palate, these phenotypes were less severe than those seen in the corresponding Tgfb3 mutants. Moreover, our results demonstrate that Trim33, a novel chromatin reader and regulator of TGF-β signaling, cooperates with Smad4 during palatogenesis. Unlike the epithelium-specific Smad4 mutants, epithelium-specific Tak1:Smad4- and Trim33:Smad4-double mutants display reduced expression of Mmp13 in palatal medial edge epithelial cells, suggesting that both of these redundant mechanisms are required for appropriate TGF-β signal transduction. Moreover, we show that inactivation of Tak1 in Trim33:Smad4 double conditional knockouts leads to the palatal phenotypes which are identical to those seen in epithelium-specific Tgfb3 mutants. To conclude, our data reveal added complexity in TGF-β signaling during palatogenesis and demonstrate that functionally redundant pathways involving Smad4, Tak1 and Trim33 regulate palatal epithelial fusion.
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48019, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Lane
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48019, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yumoto
authors.affiliation: Department of Pediatrics, Indiana University, Indianapolis, IN, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Azhar
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC, USA.
authors.forename: Maiko
authors.initials: M
authors.lastname: Inagaki
authors.affiliation: Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Yingling
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.affiliation: The Saban Research Institute of Children׳s Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48019, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48019, USA. Electronic address: vesak@umich.edu.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002459:Cell Fusion; D049109:Cell Proliferation; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D010159:Palate / Q000002:abnormalities / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D053782:Transforming Growth Factor beta3 / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D053509:Matrix Metalloproteinase 13; D051901:Smad4 Protein; D014157:Transcription Factors; D053782:Transforming Growth Factor beta3; D000099151:MAP Kinase Kinase Kinase 7; C490810:Smad4 protein, mouse; C491420:Trim33 protein, mouse
keywords: Palatogenesis; Smad4; TGF-β3 signaling; Tak1; Trim33