High impact information on Nodal

• In contrast, signaling by the growth factors Nodal and Wnt3, which are also essential during mouse gastrulation, appears to be normal in lzme embryos [1].
• Several genes (such as Nodal, Ebaf and Pitx2) have been implicated in L-R organ positioning in model organisms [2].
• Moreover, Nodal signals from the epiblast also pattern the visceral endoderm by activating the Smad2-dependent pathway required for specification of anterior identity in overlying epiblast cells [3].
• The activity of Nodal signals is regulated extracellularly by EGF-CFC cofactors and antagonists of the Lefty and Cerberus families of proteins, allowing precise control of mesoderm and endoderm formation, the positioning of the anterior-posterior axis, neural patterning and left-right axis specification [4].
• The activity of the Nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axis [5].

Biological context of Nodal

• Analogously, overexpression of Antivin or Lefty2 in zebrafish embryos blocks head and trunk mesoderm formation, a phenotype identical to that of mutants caused by loss of Nodal signaling [6].
• This enhancer is responsible for early activation of Nodal expression in the epiblast and visceral endoderm, and at later stages governs asymmetric expression during LR axis formation [7].
• The feedback loop is thus essential for maintenance of Nodal signals that selectively regulate target gene expression in a temporally and spatially controlled fashion in the mouse embryo [7].
• The mutant mice failed to express Nodal, Lefty2 and Pitx2 on the left side during embryogenesis and exhibited right isomerism [8].
• A conserved intronic enhancer (ASE), containing binding sites for the fork head transcription factor Foxh1, modulates dynamic patterns of Nodal expression during early mouse development [7].

Anatomical context of Nodal

• Thus lowering the level of Nodal signaling in the epiblast disrupts both orientation of the AP axis and specification of the definitive endoderm [7].
• Thus, unlike previous models proposed in the chick embryo in which Bmp4 suppresses left-sided gene expression, our results suggest that Bmp acts as a positive facilitator of the left-sided molecular cascade and is required for Nodal induction and maintenance in the left LPM [9].
• Our analysis shows that neural specification occurs and regional identities characteristic of the forebrain are established precociously in the Nodal-/- mutant with a sequential progression equivalent to that of wild-type embryo [10].
• Implantation of cells expressing human or mouse CFC2, or chick CFC on the right side of Hensen's node randomized heart looping without affecting expression of genes involved in left-right axis formation, including SnR, Nodal, Car, or Pitx2 [11].
• We conclude that uncleaved Nodal sustains the extraembryonic source of proprotein convertases and Bmp4 to amplify Nodal signaling in two nonredundant feedback loops with dual timescales and to localize primitive streak formation at the posterior pole [12].

Associations of Nodal with chemical compounds

• Two type I serine/threonine kinase receptors have been identified for Nodal, ALK4 and ALK7 [13].
• In this paper, we present biochemical and functional evidence that the orphan type I serine/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1) [14].

Physical interactions of Nodal

• Here we show that the neural-inducing and mesoderm-inhibiting activities of Cer-l result from specific binding to BMP and Nodal molecules, respectively [15].

Regulatory relationships of Nodal

• Ectopic Nodal expression in right LPM also induced Lefty1 expression in the floor plate [8].
• The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo [7].
• Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate [8].
• This indicates that Nodal may induce Cripto through both a signalling pathway in the embryo and induction of Bmp4 in the extraembryonic ectoderm [16].
• Here we show that the Notch signaling pathway plays a primary role in the establishment of left-right asymmetry in mice by directly regulating expression of the Nodal gene [17].

Other interactions of Nodal

• The transcription factor Foxh1 mediates Nodal signaling [8].
• Thus, chick CFC seems to have a dual function in left-right axis formation by maintaining Nodal expression in the lateral plate mesoderm and controlling expression of Lefty1 expression in the midline territory [11].
• Notably, L-R asymmetric expression of Nodal at the lateral edges of the node is still observed in Cryptic mutants, indicating that L-R specification has occurred in the node but not the lateral plate [18].
• The analysis of Nodal-/-;Gsc-/- compound mutant embryos shows that Gsc activity plays no critical role in the acquisition of forebrain characters by Nodal-deficient cells [10].
• The TGFbeta-related growth factor Nodal governs anteroposterior (AP) and left-right (LR) axis formation in the vertebrate embryo [7].

Analytical, diagnostic and therapeutic context of Nodal

• Ectopic introduction of Nodal into right LPM, by transplantation of left LPM or by electroporation of a Nodal vector, induced Nodal expression in wild-type embryos but not in the mutant [8].
• Both Nodal and Activin B expression was found in the xenograft tumor, suggesting that either ligand could be promoting tumorigenesis [19].
• When both XCR1 and XCR3 are knocked down, activation of the Nodal intracellular signal transducer, Smad2, is severely inhibited and neither gastrulation nor mesendoderm formation occurs [20].
• From the real-time PCR analysis, expression levels of some genes, such as Oct3/4, Nodal and beta-catenin, were different between two hESC lines [21].

References