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Published on: February 12, 2021
Endogenous Natural Complement Inhibitor Regulates Cardiac Development
Simon A Mortensen1, Louise L Skov2, Kasper Kjaer-Sorensen2
1Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
Insights
Mannan-binding lectin-associated protein (MAp)44 regulates cardiac development by influencing neural crest cell migration. This immune molecule
Area of Science:
- Immunology
- Developmental Biology
- Cardiology
Background:
- Congenital heart defects (CHDs) are a leading cause of perinatal mortality with unknown etiology in many cases.
- Immune molecules play critical roles in fetal development and adult homeostasis.
- Mannan-binding lectin (MBL)-associated protein (MAp)44 is an endogenous complement inhibitor.
Purpose of the Study:
- To investigate the function of MAp44 in cardiac development.
- To elucidate the role of MAp44 in regulating the MBL-associated serine protease (MASP)-3/collectin-L1/K1 complex.
- To understand the impact of MAp44 on cardiac neural crest cell migration.
Main Methods:
- Utilized zebrafish as a model organism for observing heart function and development.
- Employed knockdown and rescue strategies to study the effects of MAp44.
- Analyzed neural crest cell behavior and cardiac parameters like heart rate and output.
Main Results:
- Knockdown of embryonic MAp44 resulted in impaired cardiogenesis, reduced heart rate, and decreased cardiac output.
- Aberrant neural crest cell migration was observed in MAp44 knockdown embryos.
- MAp44 was found to compete with MASP-3 for pattern recognition molecule interaction.
- Overexpression of wild-type MAp44 rescued the observed developmental defects.
Conclusions:
- MAp44 is crucial for normal cardiac development.
- Immune molecules are integral to the orchestration of cardiac tissue formation.
- MAp44's function in regulating MASP-3 complex composition impacts cardiac neural crest cell migration.
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.
