NODAL

Nodal is a secretory is_associated_with::protein that in humans is encoded by the NODAL is_associated_with::gene which is located on is_associated_with::chromosome 10q22.1. It belongs to the Transforming Growth Factor (TGF-beta) superfamily. Like many other members of this superfamily it is involved in is_associated_with::cell differentiation in early is_associated_with::embryogenesis, playing a key role in signal transfer from the node, in the anterior is_associated_with::primitive streak, to is_associated_with::lateral plate mesoderm (LPM).

Nodal signaling is important very early in development for is_associated_with::mesoderm and is_associated_with::endoderm formation and subsequent organization of left-right axial structures. In addition, Nodal seems to have important functions in neural patterning, is_associated_with::stem cell maintenance and many other developmental processes, including left/right handedness.

Signaling
Nodal can bind type I and type II Serine/Threonine kinase receptors, with Cripto-1 acting as its co-receptor. Signaling through SMAD 2/3 and subsequent translocation of SMAD 4 to the nucleus promotes the expression of is_associated_with::genes involved in proliferation and differentiation. Nodal also further activates its own expression via a positive feedback loop. It is tightly regulated by inhibitors Lefty A, Lefty B, Cerberus, and Tomoregulin-1, which can interfere with Nodal receptor binding.

Species specific Nodal Ligands
Nodal is a widely distributed is_associated_with::cytokine. The presence of Nodal is not limited to is_associated_with::vertebrates, it is also known to be conserved in other is_associated_with::deuterostomes (is_associated_with::cephalochordates, is_associated_with::tunicates and is_associated_with::echinoderms) and is_associated_with::protostomes such as snails, but interestingly neither the nematode C. elegans (another protosome) nor the fruit fly Drosophila (an arthropode) have a copy of nodal. Although mouse and human only have one nodal gene, the zebrafish contain three nodal paralogs: squint, cyclops and southpaw, and the frog five (xnr1,2,3,5 and 6). Even though the zebrafish Nodal homologs are very similar, they have specialized to perform different roles; for instance, Squint and Cyclops are important for mesoendoderm formation, whereas the Southpaw has a major role in asymmetric heart is_associated_with::morphogenesis and visceral left-right asymmetry. Another example of protein speciation is the case of the frog where Xnr1 and Xnr2 regulate movements in gastrulation in contrast to Xnr5 and Xnr6 that are involved in mesoderm induction. In mouse, Nodal has been implicated in left-right asymmetry, neural pattering and mesoderm induction (see is_associated_with::nodal signaling).

Functions
Nodal signaling regulates is_associated_with::mesoderm formation in a species-specific manner. Thus, in is_associated_with::Xenopus, Xnr controls dorso-ventral is_associated_with::mesoderm formation along the marginal zone. In is_associated_with::zebrafish, Squint and Cyclops are responsible for animal-vegetal is_associated_with::mesoderm formation. In is_associated_with::chicken and is_associated_with::mouse, Vg1 and Nodal respectively promote primitive streak formation in the epiblast. In chick development, Nodal is expressed in is_associated_with::Koller's sickle. Studies have shown that a nodal knockout in is_associated_with::mouse causes the absence of the primitive streak and failure in the formation of is_associated_with::mesoderm, leading to developmental arrest just after is_associated_with::gastrulation.

Compared to is_associated_with::mesoderm specification, is_associated_with::endoderm specification requires a higher expression of Nodal. Here, Nodal stimulates mixer homeoproteins, which can interact with SMADs in order to up-regulate is_associated_with::endoderm specific genes and repress is_associated_with::mesoderm specific genes.

Left-right (LR) asymmetry of visceral organs in is_associated_with::vertebrates is also established through is_associated_with::nodal signaling. Whereas Nodal is initially symmetrically expressed in the is_associated_with::embryo, after is_associated_with::gastrulation, Nodal becomes asymmetrically restricted to the left side of the organism. It is highly conserved among deuterostomes. An is_associated_with::ortholog of Nodal was recently found in is_associated_with::snails and was shown to be involved in left-right asymmetry as well.

In order to enable anterior neural tissue development, Nodal signaling needs to be repressed after inducing mesendoderm and LR symmetry.

Recent research on mouse and human is_associated_with::embryonic stem cells (hESCs) indicates that Nodal seems to be involved in the maintenance of is_associated_with::stem cell self-renewal and pluripotent potentials. Thus, overexpression of Nodal in hESCs lead to the repression of cell differentiation. On the contrary, inhibition of Nodal and Activin signaling enabled the differentiation of hESCs.