Abstract
Neural crest cells migrate to the embryonic heart and transform into a small number of cardiomyocytes, but their functions in the developing and adult heart are unknown. Here, we show that neural crest derived cardiomyocytes (NC-Cms) in the zebrafish ventricle express Notch ligand jag2b, are adjacent to Notch responding cells, and persist throughout life. Genetic ablation of NC-Cms during embryogenesis results in diminished jag2b, altered Notch signaling and aberrant trabeculation patterns, but is not detrimental to early heart function or survival to adulthood. However, embryonic NC-Cm ablation results in adult fish that show severe hypertrophic cardiomyopathy (HCM), altered cardiomyocyte size, diminished adult heart capacity and heart failure in cardiac stress tests. Adult jag2b mutants have similar cardiomyopathy. Thus, we identify a cardiomyocyte population and genetic pathway that are required to prevent adult onset HCM and provide a zebrafish model of adult-onset HCM and heart failure.
Highlights
Neural crest cells migrate to the embryonic heart and transform into a small number of cardiomyocytes, but their functions in the developing and adult heart are unknown
The hypertrophic cardiomyopathy and heart failure in adults and aberrant trabeculation patterning in embryos can only be attributed to the post-migratory Neural crest (NC) that have converted to bona fide cardiomyocytes
The outcomes of ablating neural crest derived cardiomyocytes (NC-Cms) stand in striking contrast to previous studies that arbitrarily ablated large numbers of embryonic ventricular cardiomyocytes and reported no consequential effects on subsequent embryonic heart regeneration, function, and trabeculation[24,25]
Summary
Neural crest cells migrate to the embryonic heart and transform into a small number of cardiomyocytes, but their functions in the developing and adult heart are unknown. As an alternative approach to decipher NC-dependent cardiac phenotypes, we ask whether a specific population of specialized cardiomyocytes, the NC-Cms, influences cardiac development and disease, by lineage mapping and genetically ablating NC-Cms during embryogenesis. This led us to discover the roles of NCCms in regulating the patterning of the Notch pathway activation in cardiomyocytes during trabeculation, and in preventing predisposition to adult-onset hypertrophic cardiomyopathy
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