Abstract
Over the past 10 years, key genes involved in specification of left-right laterality pathways in the embryo have been defined. The read-out for misexpression of laterality genes is usually the direction of heart looping. The question of how dextral looping direction occurred mechanistically and how the heart tube bends remains unknown. It is becoming clear from our experiments and those of others that left-right differences in cell proliferation in the second heart field (anterior heart field) drives the dextral direction. Evidence is accumulating that the cytoskeleton is at the center of laterality, and the bending and rotational forces associated with heart looping. If laterality pathways are modulated upstream, the cytoskeleton, including nonmuscle myosin II (NMHC-II), is altered downstream within the cardiomyocytes, leading to looping abnormalities. The cytoskeleton is associated with important mechanosensing and signaling pathways in cell biology and development. The initiation of blood flow during the looping period and the inherent stresses associated with increasing volumes of blood flowing into the heart may help to potentiate the process. In recent years, the steps involved in this central and complex process of heart development that is the basis of numerous congenital heart defects are being unraveled.
Highlights
Heart looping is a central process in cardiac development
From analyses of invertebrate models, it appears that the unconventional myosins in association with the actin cytoskeleton has a central role in left-right determination[42], and we suggest that the actomyosin cytoskeleton have a central role in vertebrate heart looping
In early reports[26,27] we reported flectin as being only an asymmetrically expressed extracellular matrix (ECM) molecule due to its localization in the cardiac jelly, an extensive acellular region prevalent during the heart looping stages that is situated between the myocardium and endocardium
Summary
Heart looping is a central process in cardiac development. Looping in all vertebrates that have been analyzed begins with a rightward movement of the anterior part of the developing straight heart tube. At this period, the ventricular area of the heart is cephalad to the atrial region. Blood flow into the straight heart tube is initiated concomitant with initiation of myocardial contractions and of looping. After completion of looping does the four-chambered heart form. Subsequent heart development involves formation of the septa and valves, leading to parallel blood flow through the heart. It is thought that many cardiac anomalies associated with congenital heart disease arise with this process
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