Cardiac Left-Right Asymmetry

This chapter reviews mechanisms that influence left-right asymmetry in vertebrate heart development. In the formation of the parallel systemic and pulmonary circulatory systems of the heart, left-right asymmetry is an essential aspect in determining both structure and function. It is becoming clear that traditional examples such as dextrocardia, the misplacement of the heart to the right, or heterotaxia, the alteration of heart orientation with respect to other organs, are only a subset of left-right cardiac defects. More commonly, subtle defects result in misalignment of the inflow and outflow tracts of the heart, resulting in a significant spectrum of congenital defects. Left-right patterning involves over 100 genes that encode components of several major cell-cell signaling pathways, as well as transcription factors and proteins required for formation of cilia. Strikingly, several embryonic tissues outside the cardiogenic fields are essential for normal cardiac left-right patterning, including cells in the embryonic node, caudal mesoderm, lateral plate mesoderm, notochord, and ventral floorplate of the neural tube. Thus, defects in cardiac left-right development can often be part of a syndrome that also presents with cilia defects or subclinical defects in midline or neural tube patterning. The understanding of the molecular basis of left-right development has greatly expanded in the last decade. The mechanisms that generate left-right asymmetry are actively studied in several vertebrate model systems, including embryos of mice, zebrafish, frogs, medaka fish, chick and rabbit, and by genetic analysis for inherited laterality defects in humans. In addition, the noncardiac cells that are essential for cardiac left-right patterning, such as ciliated cells, midline cells, and lateral plate mesoderm are becoming better understood.