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Nodal is a secretory protein that in humans is encoded by the NODAL gene[1][2] which is located on chromosome 10q22.1.[3] It belongs to the Transforming Growth Factor (TGF-β) superfamily. Like many other members of this superfamily it is involved in cell differentiation in early embryogenesis, playing a key role in signal transfer from the node, in the anterior primitive streak, to lateral plate mesoderm (LPM).[4][5]

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).


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]


  1. 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. PMID 9354794.
  2. 2.0 2.1 "Entrez Gene: NODAL nodal homolog (mouse)".
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Strizzi L, Postovit LM, Margaryan NV, Seftor EA, Abbott DE, Seftor RE, Salomon DS, Hendrix MJ (2008). "Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression". Breast disease. 29: 91–103. PMC 3175751. PMID 19029628.
  4. 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. PMID 21419113.
  5. 5.0 5.1 Branford WW, Yost HJ (May 2004). "Nodal signaling: CrypticLefty mechanism of antagonism decoded". Current Biology. 14 (9): R341–3. doi:10.1016/j.cub.2004.04.020. PMID 15120085.
  6. 6.0 6.1 Dougan 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. PMID 12642489.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 Shen MM (March 2007). "Nodal Signaling: development and regulation". Development. 134 (6): 1023–34. doi:10.1242/dev.000166. PMID 17287255.
  8. Brandler WM, Morris AP, Evans DM, Scerri TS, Kemp JP, Timpson NJ, St Pourcain B, Smith GD, Ring SM, Stein J, Monaco AP, Talcott JB, Fisher SE, Webber C, Paracchini S (September 2013). "Common variants in left/right asymmetry genes and pathways are associated with relative hand skill". PLoS Genet. 9 (9): e1003751. doi:10.1371/journal.pgen.1003751. PMC 3772043. PMID 24068947.
  9. 9.0 9.1 9.2 Schier AF (Aug 2003). "Nodal Signaling in vertebrate development". Annual Review of Cell and Developmental Biology. 19: 589–621. doi:10.1146/annurev.cellbio.19.041603.094522. PMID 14570583.
  10. Chen, Hsu-Hsin & Geijsen, Neils (2006). "Signaling germline commitment". In Simón, Carlos & Pellicer, Antonio. Stem cells in human reproduction: basic science and therapeutic potential. CRC Press. p. 74. ISBN 978-0-415-39777-3.
  11. Chea HK, Wright CV, Swalla BJ (October 2005). "Nodal signaling and the evolution of deuterostome gastrulation". Dev. Dyn. 234 (2): 269–78. doi:10.1002/dvdy.20549. PMID 16127715.
  12. Schier AF (November 2009). "Nodal morphogens". Cold Spring Harb Perspect Biol. 1 (5): a003459. doi:10.1101/cshperspect.a003459. PMC 2773646. PMID 20066122.
  13. Baker K, Holtzman NG, Burdine RD (September 2008). "Direct and indirect roles for Nodal signaling in two axis conversions during asymmetric morphogenesis of the zebrafish heart". Proc. Natl. Acad. Sci. U.S.A. 105 (37): 13924–9. doi:10.1073/pnas.0802159105. PMC 2544555. PMID 18784369.
  14. Luxardi G, Marchal L, Thomé V, Kodjabachian L (February 2010). "Distinct Xenopus Nodal ligands sequentially induce mesendoderm and control gastrulation movements in parallel to the Wnt/PCP pathway". Development. 137 (3): 417–26. doi:10.1242/dev.039735. PMID 20056679.
  15. Schnell, Santiago. Multiscale Modeling of Developmental Systems. Retrieved 7 December 2013.
  16. 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. PMID 7924997.
  17. 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. PMID 8429908.
  18. Reissmann E, Jörnvall H, Blokzijl A, et al. (August 2001). "The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development". Genes Dev. 15 (15): 2010–22. doi:10.1101/gad.201801. PMC 312747. PMID 11485994.
  19. Hamada H, Meno C, Watanabe D, Saijoh Y (February 2002). "Establishment of vertebrate left-right asymmetry". Nat. Rev. Genet. 3 (2): 103–13. doi:10.1038/nrg732. PMID 11836504.
  20. 20.0 20.1 Grande C, Patel NH (February 2009). "Nodal signalling is involved in left-right asymmetry in snails". Nature. 457 (7232): 1007–11. doi:10.1038/nature07603. PMC 2661027. PMID 19098895.
  21. Chng Z, Vallier L, Pedersen R (2011). "Activin/ nodal signaling and pluripotency". Vitamins and hormones. 85: 38–58. doi:10.1016/B978-0-12-385961-7.00003-2. PMID 21353875.
  22. 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. PMID 20596917.

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