Functional Modulation of Cardiac Form through Regionally Confined Cell Shape Changes

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Abstract
Developing organs acquire a specific three-dimensional form that ensures their normal function. Cardiac function, for example, depends upon properly shaped chambers that emerge from a primitive heart tube. The cellular mechanisms that control chamber shape are not yet understood. Here, we demonstrate that chamber morphology develops via changes in cell morphology, and we determine key regulatory influences on this process. Focusing on the development of the ventricular chamber in zebrafish, we show that cardiomyocyte cell shape changes underlie the formation of characteristic chamber curvatures. In particular, cardiomyocyte elongation occurs within a confined area that forms the ventricular outer curvature. Because cardiac contractility and blood flow begin before chambers emerge, cardiac function has the potential to influence chamber curvature formation. Employing zebrafish mutants with functional deficiencies, we find that blood flow and contractility independently regulate cell shape changes in the emerging ventricle. Reduction of circulation limits the extent of cardiomyocyte elongation; in contrast, disruption of sarcomere formation releases limitations on cardiomyocyte dimensions. Thus, the acquisition of normal cardiomyocyte morphology requires a balance between extrinsic and intrinsic physical forces. Together, these data establish regionally confined cell shape change as a cellular mechanism for chamber emergence and as a link in the relationship between form and function during organ morphogenesis. As organs develop, they acquire a characteristic shape; the factors governing this complex process, however, are not understood. Shape may be sculpted by cell movement, cell division, or changes in cell size and shape, all of which can be influenced by the local environment. Here we investigate heart formation to understand how organs develop. The heart appears as a simple tube early in development; later, the tube walls bulge outward to form the cardiac chambers. Using transgenic zebrafish in which we can watch individual cardiac cells, we found that cells change size and shape, enlarging and elongating to form the bulges in the heart tube and eventually the chambers. Since the heart is beating as it develops, we asked whether cardiac function influences cell shape. Using zebrafish mutants with functional defects, we found that both blood flow and cardiac contractility influence cardiac cell shape. We propose that a balance of the cell's internal forces (through contractility) with external forces (such as blood flow) is necessary to create the cell shapes that generate chamber curvatures. Disruption of this balance may underlie the aberrations observed in some types of heart disease.