Nodal signaling is important very early in development for mesoderm and endoderm formation and subsequent organization of left-right axial structures.[2][6][7] In addition, Nodal seems to have important functions in neural patterning, stem cell maintenance[3][7] and many other developmental processes, including left/right handedness.[6][8]
Nodal can bind type I and type II Serine/Threonine kinase receptors, with Cripto-1 acting as its co-receptor.[9] Signaling through SMAD 2/3 and subsequent translocation of SMAD 4 to the nucleus promotes the expression of genes involved in proliferation and differentiation.[3] Nodal also further activates its own expression via a positive feedback loop.[7][9] It is tightly regulated by inhibitors Lefty A, Lefty B, Cerberus, and Tomoregulin-1, which can interfere with Nodal receptor binding.[5][7]
Species specific Nodal Ligands
Nodal is a widely distributed cytokine.[10] The presence of Nodal is not limited to vertebrates, it is also known to be conserved in other deuterostomes (cephalochordates, tunicates and echinoderms) and protostomes such as snails, but neither the nematode C. elegans (another protosome) nor the fruit fly Drosophila (an arthropod) have a copy of nodal.[11][12] 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 morphogenesis and visceral left-right asymmetry.[13] 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.[14] In mouse, Nodal has been implicated in left-right asymmetry, neural pattering and mesoderm induction (see nodal signaling).
Functions
Nodal signaling regulates mesoderm formation in a species-specific manner. Thus, in Xenopus, Xnr controls dorso-ventral mesoderm formation along the marginal zone. In zebrafish, Squint and Cyclops are responsible for animal-vegetal mesoderm formation. In chicken and mouse, Vg1 and Nodal respectively promote primitive streak formation in the epiblast.[7] In chick development, Nodal is expressed in Koller's sickle.[15] Studies have shown that a nodal knockout in mouse causes the absence of the primitive streak and failure in the formation of mesoderm, leading to developmental arrest just after gastrulation.[16][17][18]
Compared to mesoderm specification, endoderm specification requires a higher expression of Nodal. Here, Nodal stimulates mixer homeoproteins, which can interact with SMADs in order to up-regulate endoderm specific genes and repress mesoderm specific genes.[7]
Left-right (LR) asymmetry of visceral organs in vertebrates is also established through nodal signaling. Whereas Nodal is initially symmetrically expressed in the embryo, after gastrulation, Nodal becomes asymmetrically restricted to the left side of the organism.[3][7] It is highly conserved among deuterostomes.[19][20] An ortholog of Nodal was found in snails and was shown to be involved in left-right asymmetry as well in 2008.[20]
In order to enable anterior neural tissue development, Nodal signaling needs to be repressed after inducing mesendoderm and LR symmetry.[7][9]
Recent research on mouse and human embryonic stem cells (hESCs) indicates that Nodal seems to be involved in the maintenance of stem cell self-renewal and pluripotent potentials.[3][7][21][22] Thus, overexpression of Nodal in hESCs lead to the repression of cell differentiation.[7] On the contrary, inhibition of Nodal and Activin signaling enabled the differentiation of hESCs.[3]
References
↑Gebbia M, Ferrero GB, Pilia G, Bassi MT, Aylsworth A, Penman-Splitt M, Bird LM, Bamforth JS, Burn J, Schlessinger D, Nelson DL, Casey B (Dec 1997). "X-linked situs abnormalities result from mutations in ZIC3". Nat Genet. 17 (3): 305–8. doi:10.1038/ng1197-305. PMID9354794.
↑Kawasumi A, Nakamura T, Iwai N, Yashiro K, Saijoh Y, Belo JA, Shiratori H, Hamada H (May 2011). "Left-right asymmetry in the level of active Nodal protein produced in the node is translated into left-right asymmetry in the lateral plate of mouse embryos". Dev. Biol. 353 (2): 321–30. doi:10.1016/j.ydbio.2011.03.009. PMID21419113.
↑ 6.06.1Dougan ST, Warga RM, Kane DA, Schier AF, Talbot WS (May 2003). "The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm". Development. 130 (9): 1837–51. doi:10.1242/dev.00400. PMID12642489.
↑Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, Robertson EJ (July 1994). "A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse". Development. 120 (7): 1919–28. PMID7924997.
↑Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR (February 1993). "Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation". Nature. 361 (6412): 543–7. doi:10.1038/361543a0. PMID8429908.
↑Fei T, Chen YG (Apr 2010). "Regulation of embryonic stem cell self-renewal and differentiation by TGF-beta family signaling". Science China Life Sciences. 53 (4): 497–503. doi:10.1007/s11427-010-0096-2. PMID20596917.
Roberts HJ, Hu S, Qiu Q, et al. (2003). "Identification of novel isoforms of activin receptor-like kinase 7 (ALK7) generated by alternative splicing and expression of ALK7 and its ligand, Nodal, in human placenta". Biol. Reprod. 68 (5): 1719–26. doi:10.1095/biolreprod.102.013045. PMID12606401.
Munir S, Xu G, Wu Y, et al. (2004). "Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells". J. Biol. Chem. 279 (30): 31277–86. doi:10.1074/jbc.M400641200. PMID15150278.
Besser D (2004). "Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3". J. Biol. Chem. 279 (43): 45076–84. doi:10.1074/jbc.M404979200. PMID15308665.
Bamforth SD, Bragança J, Farthing CR, et al. (2004). "Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway". Nat. Genet. 36 (11): 1189–96. doi:10.1038/ng1446. PMID15475956.
Vallier L, Reynolds D, Pedersen RA (2005). "Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway". Dev. Biol. 275 (2): 403–21. doi:10.1016/j.ydbio.2004.08.031. PMID15501227.
Hart AH, Willson TA, Wong M, et al. (2005). "Transcriptional regulation of the homeobox gene Mixl1 by TGF-beta and FoxH1". Biochem. Biophys. Res. Commun. 333 (4): 1361–9. doi:10.1016/j.bbrc.2005.06.044. PMID15982639.
Vallier L, Alexander M, Pedersen RA (2006). "Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells". J. Cell Sci. 118 (Pt 19): 4495–509. doi:10.1242/jcs.02553. PMID16179608.
Fei T, Chen YG (Apr 2010). "Regulation of embryonic stem cell self-renewal and differentiation by TGF-beta family signaling". Science China Life Sciences. 53 (4): 497–503. doi:10.1007/s11427-010-0096-2. PMID20596917.