Biology:NODAL

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 beta (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]

Signaling

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

  1. ↑ "X-linked situs abnormalities result from mutations in ZIC3". Nat Genet 17 (3): 305–8. Dec 1997. doi:10.1038/ng1197-305. PMID 9354794. 
  2. ↑ 2.0 2.1 "Entrez Gene: NODAL nodal homolog (mouse)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4838. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression". Breast Disease 29: 91–103. 2008. doi:10.3233/bd-2008-29110. PMID 19029628. 
  4. ↑ "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. May 2011. doi:10.1016/j.ydbio.2011.03.009. PMID 21419113. 
  5. ↑ 5.0 5.1 "Nodal signaling: CrypticLefty mechanism of antagonism decoded". Current Biology 14 (9): R341-3. May 2004. doi:10.1016/j.cub.2004.04.020. PMID 15120085. 
  6. ↑ 6.0 6.1 "The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm". Development 130 (9): 1837–51. May 2003. 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. ↑ "Common variants in left/right asymmetry genes and pathways are associated with relative hand skill". PLOS Genet. 9 (9): e1003751. September 2013. doi:10.1371/journal.pgen.1003751. 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". Stem cells in human reproduction: basic science and therapeutic potential. CRC Press. p. 74. ISBN 978-0-415-39777-3. https://books.google.com/books?id=rShYiEGhvt4C&pg=PA74. 
  11. ↑ "Nodal signaling and the evolution of deuterostome gastrulation". Dev. Dyn. 234 (2): 269–78. October 2005. 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. PMID 20066122. 
  13. ↑ "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. September 2008. doi:10.1073/pnas.0802159105. PMID 18784369. Bibcode: 2008PNAS..10513924B. 
  14. ↑ "Distinct Xenopus Nodal ligands sequentially induce mesendoderm and control gastrulation movements in parallel to the Wnt/PCP pathway". Development 137 (3): 417–26. February 2010. doi:10.1242/dev.039735. PMID 20056679. 
  15. ↑ Schnell, Santiago (18 December 2007). Multiscale Modeling of Developmental Systems. ISBN 9780080556536. https://books.google.com/books?id=wc6irQKViJcC&q=analogous+system+to+koller%27s+sickle&pg=PA167. Retrieved 7 December 2013. 
  16. ↑ "A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse". Development 120 (7): 1919–28. July 1994. doi:10.1242/dev.120.7.1919. PMID 7924997. 
  17. ↑ "Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation". Nature 361 (6412): 543–7. February 1993. doi:10.1038/361543a0. PMID 8429908. Bibcode: 1993Natur.361..543Z. https://zenodo.org/record/1233139. 
  18. ↑ "The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development". Genes Dev. 15 (15): 2010–22. August 2001. doi:10.1101/gad.201801. PMID 11485994. 
  19. ↑ "Establishment of vertebrate left-right asymmetry". Nat. Rev. Genet. 3 (2): 103–13. February 2002. doi:10.1038/nrg732. PMID 11836504. 
  20. ↑ 20.0 20.1 "Nodal signalling is involved in left-right asymmetry in snails". Nature 457 (7232): 1007–11. February 2009. doi:10.1038/nature07603. PMID 19098895. Bibcode: 2009Natur.457.1007G. 
  21. ↑ "Activin/ nodal signaling and pluripotency". Vitamins and Hormones 85: 38–58. 2011. doi:10.1016/B978-0-12-385961-7.00003-2. ISBN 9780123859617. PMID 21353875. 
  22. ↑ "Regulation of embryonic stem cell self-renewal and differentiation by TGF-beta family signaling". Science China Life Sciences 53 (4): 497–503. Apr 2010. doi:10.1007/s11427-010-0096-2. PMID 20596917. 

Further reading

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