title: Endogenous Natural Complement Inhibitor Regulates Cardiac Development.
abstract: Congenital heart defects are a major cause of perinatal mortality and morbidity, affecting >1% of all live births in the Western world, yet a large fraction of such defects have an unknown etiology. Recent studies demonstrated surprising dual roles for immune-related molecules and their effector mechanisms during fetal development and adult homeostasis. In this article, we describe the function of an endogenous complement inhibitor, mannan-binding lectin (MBL)-associated protein (MAp)44, in regulating the composition of a serine protease-pattern recognition receptor complex, MBL-associated serine protease (MASP)-3/collectin-L1/K1 hetero-oligomer, which impacts cardiac neural crest cell migration. We used knockdown and rescue strategies in zebrafish, a model allowing visualization and assessment of heart function, even in the presence of severe functional defects. Knockdown of embryonic expression of MAp44 caused impaired cardiogenesis, lowered heart rate, and decreased cardiac output. These defects were associated with aberrant neural crest cell behavior. We found that MAp44 competed with MASP-3 for pattern recognition molecule interaction, and knockdown of endogenous MAp44 expression could be rescued by overexpression of wild-type MAp44. Our observations provide evidence that immune molecules are centrally involved in the orchestration of cardiac tissue development.
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Simon A
authors.identifier: 0000-0001-9013-1802
authors.initials: SA
authors.lastname: Mortensen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Louise L
authors.initials: LL
authors.lastname: Skov
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Kjaer-Sorensen
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Annette G
authors.initials: AG
authors.lastname: Hansen
authors.affiliation: Department of Cancer and Inflammation Research, University of Southern Denmark, DK-5000 Odense, Denmark; and.
authors.forename: Søren
authors.identifier: 0000-0002-8186-4630
authors.initials: S
authors.lastname: Hansen
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnæs-Hansen
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Jensenius
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; sdegn@biomed.au.dk.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Søren E
authors.initials: SE
authors.lastname: Degn
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques; D006321:Heart / Q000196:embryology*; D006801:Humans; D017403:In Situ Hybridization; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins; D050606:Mannose-Binding Protein-Associated Serine Proteases