The Nodal Signaling Pathway And Its Effect On The Great Arteries

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In light of the functional importance of the Nodal signaling pathway and its effect on the great arteries, it is pertinent to understand how Nodal is regulated. To this end, Lefty2 is one of many downstream target genes and transcriptional end products regulated by the Smad-FOXH1 complex (Shen, 2007). Other target products include Pitx2, FoxA2 and Lhx1 (Shen, 2007). The expression of Left2 plays a crucial role in down regulating Nodal signaling during establishment of L-R axis through feedback inhibition of both Nodal & CFC1 (Branford et al., 2002; Feldman et al., 2002; Meno et al., 1999; Besser et al., 2004). Meno et al. (2001) demonstrated that mice lacking asymmetrical expression of lefty2 exhibited severe cardiac defects including transposition of the great arteries and double outlet of the right ventricle. Lefty2 deficiency results in extending the range and diffusion of Nodal, exerting further transcriptional influence across the node and into the right lateral plate mesoderm. Additionally, the level of Pitx2 was shown to be bilaterally amplified in the absence of Lefty2 (Meno et al., 2001). The Pitx2 protein is a bicoid-related homeodomain transcription factor involved in left-right asymmetric cardiogenesis as well as development of eye and craniofacial regions (Hjalt et al., 2000). Most interestingly, experimental murine models utilizing targeted loss of Pitx2 function resulted in severe cardiovascular defects including transposition of the great arteries,

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