Mutation of weak atrium/atrial myosin heavy chain disrupts atrial function and influences ventricular morphogenesis in zebrafish.
The embryonic vertebrate heart is composed of two major chambers, a ventricle and an atrium, each of which has a characteristic size, shape and functional capacity that contributes to efficient circulation. Chamber-specific gene expression programs are likely to regulate key aspects of chamber formation. Here, we demonstrate that epigenetic factors also have a significant influence on chamber morphogenesis. Specifically, we show that an atrium-specific contractility defect has a profound impact on ventricular development. We find that the zebrafish locus weak atrium encodes an atrium-specific myosin heavy chain that is required for atrial myofibrillar organization and contraction. Despite their atrial defects, weak atrium mutants can maintain circulation through ventricular contraction. However, the weak atrium mutant ventricle becomes unusually compact, exhibiting a thickened myocardial wall, a narrow lumen and changes in myocardial gene expression. As weak atrium/atrial myosin heavy chain is expressed only in the atrium, the ventricular phenotypes in weak atrium mutants represent a secondary response to atrial dysfunction. Thus, not only is cardiac form essential for cardiac function, but there also exists a reciprocal relationship in which function can influence form. These findings are relevant to our understanding of congenital defects in cardiac chamber morphogenesis.
Developmental Genetics Program and Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Eli
E
Berdougo
Hope
H
Coleman
Diana H
DH
Lee
Didier Y R
DY
Stainier
Deborah
D
Yelon
D000818:Animals; D016275:Atrial Function / Q000502:physiology*; D024743:Atrial Myosins / Q000235:genetics / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D006321:Heart / Q000502:physiology; D006325:Heart Atria / Q000196:embryology* / Q000378:metabolism / Q000648:ultrastructure; D006352:Heart Ventricles / Q000196:embryology* / Q000378:metabolism / Q000648:ultrastructure; D009024:Morphogenesis; D009154:Mutation; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D029961:Zebrafish Proteins; C481025:myh6 protein, zebrafish; D009320:Atrial Natriuretic Factor; D024743:Atrial Myosins; D018995:Myosin Heavy Chains