title: Heparan Sulfate Biosynthesis Enzyme, Ext1, Contributes to Outflow Tract Development of Mouse Heart via Modulation of FGF Signaling.
abstract: Glycosaminoglycans are important regulators of multiple signaling pathways. As a major constituent of the heart extracellular matrix, glycosaminoglycans are implicated in cardiac morphogenesis through interactions with different signaling morphogens. Ext1 is a glycosyltransferase responsible for heparan sulfate synthesis. Here, we evaluate the function of Ext1 in heart development by analyzing Ext1 hypomorphic mutant and conditional knockout mice. Outflow tract alignment is sensitive to the dosage of Ext1. Deletion of Ext1 in the mesoderm induces a cardiac phenotype similar to that of a mutant with conditional deletion of UDP-glucose dehydrogenase, a key enzyme responsible for synthesis of all glycosaminoglycans. The outflow tract defect in conditional Ext1 knockout(Ext1f/f:Mesp1Cre) mice is attributable to the reduced contribution of second heart field and neural crest cells. Ext1 deletion leads to downregulation of FGF signaling in the pharyngeal mesoderm. Exogenous FGF8 ameliorates the defects in the outflow tract and pharyngeal explants. In addition, Ext1 expression in second heart field and neural crest cells is required for outflow tract remodeling. Our results collectively indicate that Ext1 is crucial for outflow tract formation in distinct progenitor cells, and heparan sulfate modulates FGF signaling during early heart development.
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
authors: Rui
authors: R
authors: Zhang
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
authors: Peijuan
authors: P
authors: Cao
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Zhongzhou
authors: Z
authors: Yang
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
authors: Zhenzhen
authors: Z
authors: Wang
authors: Institute of Biomedical and Pharmaceutical Technology, Fuzhou University, Fuzhou, China.
authors: Jiu-Lin
authors: JL
authors: Wu
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
authors: Yan
authors: Y
authors: Chen
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
authors: Yi
authors: Y
authors: Pan
mesh_terms: D000818:Animals; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006321:Heart / Q000196:embryology* / Q000254:growth & development; D006497:Heparan Sulfate / Q000096:biosynthesis / Q000502:physiology; D017403:In Situ Hybridization; D059630:Mesenchymal Stem Cells / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology; D017351:N-Acetylglucosaminyltransferases / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000099058:Exostosin 1
chemical_list: D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1