Diffusion of Nodal Signaling Activity in the Absence of the Feedback Inhibitor Lefty2

Abstract

The role of Lefty2 in left-right patterning was investigated by analysis of mutant mice that lack asymmetric expression of lefty2. These animals exhibited various situs defects including left isomerism. The asymmetric expression of nodal was prolonged and the expression of Pitx2 was upregulated in the mutant embryos. The absence of Lefty2 conferred on Nodal the ability to diffuse over a long distance. Thus, Nodal-responsive genes, including Pitx2, that are normally expressed on the left side were expressed bilaterally in the mutant embryos, even though nodal expression was confined to the left side. These results suggest that Nodal is a long-range signaling molecule but that its range of action is normally limited by the feedback inhibitor Lefty2.

Xenopus nodal related-1 is indispensable only for left-right axis determination

“…It is possible that some secretory factor(s) induces the posterior bilateral Xnr-1 expression, but the physiological role of this bilateral expression is unknown. Because Nodal is a diffusive secretory signaling molecule (Meno et al, 1999;Meno et al, 2001;Sakuma et al, 2002), it is reasonable to suppose that the posterior bilateral Xnr-1 expression supplies the Xnr-1 ligand that diffuses toward the left LPM to induce Xnr-1 expression by an autoregulatory feedback mechanism. Actually, we show here that right LPM can transduce a Nodal (Xnr-1) signal (Figs.…”

Mice with mutations in Mahogunin ring finger‐1 (Mgrn1) exhibit abnormal patterning of the left–right axis

“…Nodal in the left LPM acts as a left-side determinant and activates Lefty2 expression (Yamamoto et al, 2003). In the absence of Lefty1 or Lefty2, early Nodal expression in the LPM is asymmetric but it subsequently becomes bilateral (Meno et al, , 2001. Abnormal expression of any of these genes typically results in LR patterning defects.…”

BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4

“…This complex phosphorylates intracellular SMAD2 and SMAD3, which associate with the common TGF␤/NODAL/BMP (bone morphogenetic protein) pathway SMAD, SMAD4, and forkhead transcription factor FOXH1, to regulate downstream target genes (Shen 2007). In the LR pathway, Nodal is first expressed in crown cells of the node at late primitive streak stages and this is required to initiate Nodal expression in the left LPM adjacent to the node, where it then mediates propagation of a left-sided cascade of gene expression cranially and caudally through a positive regulatory loop (Saijoh et al 2000(Saijoh et al , 2003Meno et al 2001;Brennan et al 2002;Norris et al 2002). Current evidence suggests that NODAL expressed from the node is directly responsible for activating Nodal in the LPM (Tanaka et al 2007).…”