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. ... More
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.
