Mutation ofweak atrium/atrial myosin heavy chaindisrupts atrial function and influences ventricular morphogenesis in zebrafish

Abstract

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 chainis 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.

Illuminating cardiac development: Advances in imaging add new dimensions to the utility of zebrafish genetics

“…During remodeling of the primitive heart tube, the ventricular myocardial wall thickens, supporting extensive trabeculation that is largely absent in the atrium [11]. In addition to displaying unique morphologies, the cardiac chambers are also molecularly distinct; for instance, they express chamber-specific myosin heavy chain genes, vmhc in the ventricle and amhc in the atrium [12,13]. The formation of cardiac chambers has its roots in the specification and patterning of cardiac progenitors (CPs) [14].…”

“…Epigenetic influences, such as the biomechanical forces created by blood flow, also contribute to the formation of chamber shape. The zebrafish locus weak atrium encodes an atrium-specific myosin heavy chain (amhc) that is required for atrial contractility [13]. In addition to atrial defects and the consequent reduction in blood flow, weak atrium mutants also display ventricular defects: the mutant ventricle acquires an unusually small shape without characteristic chamber curvatures.…”

“…In addition to atrial defects and the consequent reduction in blood flow, weak atrium mutants also display ventricular defects: the mutant ventricle acquires an unusually small shape without characteristic chamber curvatures. Since amhc is expressed only in the atrium [13], this ventricular phenotype represents a secondary consequence of atrial dysfunction, presumably reflecting an impact of normal hemodynamics on chamber ballooning.…”

“…Several of these mutations disrupt genes encoding components of the sarcomere, including pickwick (titin) [46], tell tale heart (cardiac myosin light chain 2) [47], weak atrium (amhc) [13], cardiofunk (actc1) [41], and silent heart (tnnt2) [48], and lead to problems with sarcomere assembly or maintenance. Other mutations in this category affect genes encoding components of the electrical conduction system that controls cardiomyocyte depolarization and repolarization.…”

Mécanotransduction des forces hémodynamiques et organogenèse

“…Serluca et al [5], ainsi qu'une très récente étude chez le poisson zèbre [24], montrent l'importance, jusque-là sous-estimée, du contrôle épigénétique par stimulus mécanique dans l'organogenèse, en particulier cardiaque. Cela permet d'émettre l'hypothèse qu'une part non négligeable des cardiopathies et autres anomalies de l'organogenèse observées chez les mutants du poisson zèbre, et par extrapolation chez l'homme, pourrait résulter d'une altération de ce processus ou de processus similaires.…”