title: Galnt1 is required for normal heart valve development and cardiac function.
abstract: Congenital heart valve defects in humans occur in approximately 2% of live births and are a major source of compromised cardiac function. In this study we demonstrate that normal heart valve development and cardiac function are dependent upon Galnt1, the gene that encodes a member of the family of glycosyltransferases (GalNAc-Ts) responsible for the initiation of mucin-type O-glycosylation. In the adult mouse, compromised cardiac function that mimics human congenital heart disease, including aortic and pulmonary valve stenosis and regurgitation; altered ejection fraction; and cardiac dilation, was observed in Galnt1 null animals. The underlying phenotype is aberrant valve formation caused by increased cell proliferation within the outflow tract cushion of developing hearts, which is first detected at developmental stage E11.5. Developing valves from Galnt1 deficient animals displayed reduced levels of the proteases ADAMTS1 and ADAMTS5, decreased cleavage of the proteoglycan versican and increased levels of other extracellular matrix proteins. We also observed increased BMP and MAPK signaling. Taken together, the ablation of Galnt1 appears to disrupt the formation/remodeling of the extracellular matrix and alters conserved signaling pathways that regulate cell proliferation. Our study provides insight into the role of this conserved protein modification in cardiac valve development and may represent a new model for idiopathic valve disease.
authors.affiliation: Developmental Glycobiology Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States of America.
authors.forename: E
authors.initials: E
authors.lastname: Tian
authors.affiliation: Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States of America.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Stevens
authors.affiliation: Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guan
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States of America.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Springer
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States of America.
authors.forename: Stasia A
authors.initials: SA
authors.lastname: Anderson
authors.affiliation: Division of Veterinary Resources, National Institutes of Health, Bethesda, United States of America.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States of America.
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.affiliation: Developmental Glycobiology Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States of America.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Ten Hagen
authors.affiliation: Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States of America.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Tabak
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071097:ADAMTS1 Protein; D000071116:ADAMTS5 Protein; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000503:physiopathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006351:Heart Valves / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics* / Q000378:metabolism*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; D000071116:ADAMTS5 Protein; D016326:Extracellular Matrix Proteins; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C486323:Adamts1 protein, mouse; C498489:Adamts5 protein, mouse