Nodal Signaling and Congenital Heart Defects

Excerpt

Nodal is a TGF-β family member ligand that is critical for early embryonic patterning in vertebrates. Nodal signaling functions through core TGF-β receptors to activate a Smad transcription factor signaling cascade. However, unlike other TGF-β ligands, Nodal signaling requires an additional co-receptor of the EGF-CFC family to activate intracellular signaling. Nodal signaling is also subject to extensive negative regulation by Lefty and other factors. Work in numerous model organisms, including mouse, chicken, and zebrafish, established that Nodal signaling plays an essential role during germ layer formation, anterior-posterior axis patterning, and left-right axis determination. Incomplete or delayed loss of Nodal signaling results in defective organogenesis and birth defects, including congenital heart defects, and clinical studies have linked aberrant Nodal signaling in humans with many common congenital malformations, including congenital heart defects. Congenital heart defects associated with disrupted Nodal signaling in mammals include those that arise due to global defects in left-right patterning of the embryo, such as heterotaxy. Other Nodal-associated heart defects appear to occur as more subtle isolated malformations of the great arteries and atrioventricular septum, which may not be related to overall perturbations in laterality. A more detailed understanding of the Nodal signaling pathway and its targets in the heart is required to more fully understand the etiology of Nodal signaling pathway-associated congenital heart defects.