Nodal signaling pathway

The nodal signaling pathway is a signal transduction pathway important in pattern formation and differentiation during embryo development.The nodal gene was originally discovered by Conlon et al. by retroviral mutation in mice which led to the isolation of a gene that interfered with normal mouse gastrulation and embryo development. Further study of this gene by Zhou et al. showed that the nodal genes encode a secreted signaling peptide that was sufficient to induce mesoderm cells in the mouse embryo. This was an important finding as many other factors had been implicated in the formation of mesoderm in Xenopus whereas the difficulty of removal of these factors due to embryonic lethality and maternal contribution of genes had kept the ability to assay the knock out phenotypes elusive. Further studies of nodal signaling in other vertebrates such as Cyclops and Squint in zebrafish proved that nodal signaling is adequate to induce mesoderm in all vertebrates.The Lefty proteins, divergent members of the TGFβ superfamily of proteins, act as extracellular antagonists of nodal signaling. Expression studies of the lefty homologue, antivin, in zebrafish show that lefty likely acts as a competitive inhibitor of nodal signaling. Overexpression of lefty leads to a phenotype similar to a nodal knockout while overexpression of the activin (nodal-related protein) receptor or even the receptor extracellular domain can rescue the phenotype. As the induction of lefty is dependent upon nodal expression, lefty acts a classic feedback inhibitor for nodal signaling. Like nodals, all vertebrates have at least one lefty gene while many, such as zebrafish and mouse, have two unique lefty genes.Multiple studies have established that Nodal signal is required for the induction of most mesodermal and endodermal cell types and Squint/Cyclops knockouts in Zebrafish do not develop notochord, heart, kidneys or even blood. The origin and expression pattern of the nodal signaling proteins differs in different species. Mammalian nodal signaling is initiated ubiquitously in epiblast cells and is maintained by autoregulatory signaling of Wnt3 and limited by the induction of antagonists such as Cerberus-like and lefty. Studies in Xenopus have found that xnr expression (the Xenopus nodal) is induced by VegT at the vegetal pole and nodals spread to the blastula. Xnr expression is stabilized by the presence of β-catenin. This information raises the question of how nodal signaling leads to the induction of both endoderm and mesoderm. The answer comes in form of a gradient of nodal protein. Temporal and spatial differences in nodal signaling will result in different cell fates. With the addition of antagonists and variable range of different nodals, a map of cell fates including both mesoderm and endoderm can be drawn for the embryo. However, it is unclear whether nodal signaling is summated or if cells respond to the amplitude of the signal.