Abstract

Left-right patterning is among the least well understood of the three axes defining the body plan, and yet it is of no less importance, with left-right patterning defects causing structural birth defects with high morbidity and mortality, such as in complex congenital heart disease, biliary atresia, or intestinal malrotation. The cell signaling pathways that govern left-right asymmetry are highly conserved and involved multiple components of the transforming growth factor beta (TGFβ) superfamily of cell signaling molecules. Central to left-right patterning is the differential activation of Nodal on the left and bone morphogenetic protein (BMP) signaling on the right. In addition, a plethora of other cell signaling pathways including sonic hedgehog (Shh), fibroblast growth factor (FGF), and Notch also contribute to the regulation of left-right patterning. In vertebrate embryos such as the mouse, frog, or zebrafish, the specification of left-right identity requires the left-right organizer (LRO) containing cells with motile and primary cilia. Cilia-generated flow plays an important role in the left-sided propagation of Nodal signaling. Ultimately, it is the left-sided expression of the transcription factor paired-like homeodomain 2 (Pitx2) that drives visceral organ asymmetry. Interestingly, while this overall scheme for left-right patterning is well conserved evolutionarily, are striking differences that suggests caution in broadly generalizing conclusions on the molecular pathways regulating left-right patterning.

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