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{{Infobox_gene}}
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'''Nodal''' is a secretory [[protein]] that in humans is encoded by the ''NODAL'' [[gene]]<ref name="pmid9354794">{{cite journal |vauthors=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 | title = X-linked situs abnormalities result from mutations in ZIC3 | journal = Nat Genet | volume = 17 | issue = 3 | pages = 305–8 |date=Dec 1997 | pmid = 9354794 | pmc =  | doi = 10.1038/ng1197-305 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NODAL nodal homolog (mouse)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4838| accessdate = }}</ref> which is located on [[chromosome 10]]q22.1.<ref name="Strizzi">{{cite journal |vauthors=Strizzi L, Postovit LM, Margaryan NV, Seftor EA, Abbott DE, Seftor RE, Salomon DS, Hendrix MJ | title = Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression | journal = Breast disease | volume = 29 | pages = 91–103 | year = 2008 | month = | pmid = 19029628 | pmc = 3175751 | doi = }}</ref> It belongs to the Transforming Growth Factor ([[Tgf 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).<ref name="pmid21419113">{{cite journal |vauthors=Kawasumi A, Nakamura T, Iwai N, Yashiro K, Saijoh Y, Belo JA, Shiratori H, Hamada H | title = 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 | journal = Dev. Biol. | volume = 353 | issue = 2 | pages = 321–30 |date=May 2011 | pmid = 21419113 | doi = 10.1016/j.ydbio.2011.03.009  }}</ref><ref name="Branford">{{cite journal |vauthors=Branford WW, Yost HJ | title = Nodal signaling: CrypticLefty mechanism of antagonism decoded | journal = Current Biology | volume = 14 | issue = 9 | pages = R341-3 |date=May 2004 | pmid = 15120085 | pmc = | doi = 10.1016/j.cub.2004.04.020 }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
Nodal signaling is important very early in [[Developmental biology|development]] for [[mesoderm]] and [[endoderm]] formation and subsequent organization of left-right axial structures.<ref name="entrez"/><ref name="Dougan_2003">{{cite journal |vauthors=Dougan ST, Warga RM, Kane DA, Schier AF, Talbot WS | title = The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm | journal = Development | volume = 130 | issue = 9 | pages = 1837–51 |date=May 2003 | pmid = 12642489 | doi = 10.1242/dev.00400| url = | issn = }}</ref><ref name="Shen">{{cite journal | author = Shen MM | title = Nodal Signaling: development and regulation | journal = Development | volume = 134 | issue = 6 | pages = 1023–34 |date=March 2007 | pmid = 17287255 | doi = 10.1242/dev.000166 }}</ref> In addition, Nodal seems to have important functions in neural patterning, [[stem cell]] maintenance<ref name="Strizzi"/><ref name="Shen"/> and many other developmental processes, including left/right [[handedness#genetic factors|handedness]].<ref name="Dougan_2003"/><ref name="pmid24068947">{{cite journal |vauthors=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 | title = Common variants in left/right asymmetry genes and pathways are associated with relative hand skill | journal = PLoS Genet. | volume = 9 | issue = 9 | pages = e1003751 |date=September 2013 | pmid = 24068947 | pmc = 3772043 | doi = 10.1371/journal.pgen.1003751 }}</ref>
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Nodal homolog (mouse)
| HGNCid = 7865
| Symbol = NODAL
| AltSymbols =; MGC138230
| OMIM = 601265
| ECnumber =
| Homologene = 8417
| MGIid = 97359
| Function = {{GNF_GO|id=GO:0005125 |text = cytokine activity}} {{GNF_GO|id=GO:0008083 |text = growth factor activity}}
| Component = {{GNF_GO|id=GO:0005615 |text = extracellular space}}
| Process = {{GNF_GO|id=GO:0001701 |text = in utero embryonic development}} {{GNF_GO|id=GO:0001947 |text = heart looping}} {{GNF_GO|id=GO:0002085 |text = repression of premature neural plate formation}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0007368 |text = determination of left/right symmetry}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}} {{GNF_GO|id=GO:0009952 |text = anterior/posterior pattern formation}} {{GNF_GO|id=GO:0019827 |text = stem cell maintenance}} {{GNF_GO|id=GO:0042074 |text = cell migration involved in gastrulation}} {{GNF_GO|id=GO:0045165 |text = cell fate commitment}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4838
    | Hs_Ensembl = ENSG00000156574
    | Hs_RefseqProtein = NP_060525
    | Hs_RefseqmRNA = NM_018055
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 10
    | Hs_GenLoc_start = 71862077
    | Hs_GenLoc_end = 71871429
    | Hs_Uniprot = Q96S42
    | Mm_EntrezGene = 18119
    | Mm_Ensembl = ENSMUSG00000037171
    | Mm_RefseqmRNA = NM_013611
    | Mm_RefseqProtein = NP_038639
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 10
    | Mm_GenLoc_start = 60813645
    | Mm_GenLoc_end = 60820694
    | Mm_Uniprot = A0PK81
  }}
}}
'''Nodal homolog (mouse)''', also known as '''NODAL''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: NODAL nodal homolog (mouse)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4838| accessdate = }}</ref>


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== Signaling ==
{{PBB_Summary
{{Main|Nodal signaling}}
| section_title =  
Nodal can bind type I and type II Serine/Threonine kinase receptors, with Cripto-1 acting as its co-receptor.<ref name="Schier">{{cite journal | author = Schier AF | title = Nodal Signaling in vertebrate development | journal = Annual Review of Cell and Developmental Biology | volume = 19 | pages = 589–621 |date=Aug 2003 | pmid = 14570583 | doi = 10.1146/annurev.cellbio.19.041603.094522 }}</ref> Signaling through [[SMAD (protein)|SMAD]] 2/3 and subsequent translocation of [[SMAD (protein)|SMAD]] 4 to the nucleus promotes the expression of [[gene]]s involved in proliferation and differentiation.<ref name="Strizzi"/> Nodal also further activates its own expression via a positive feedback loop.<ref name="Shen"/><ref name="Schier"/> It is tightly regulated by inhibitors [[Lefty (protein)|Lefty]] A, [[Lefty (protein)|Lefty]] B, Cerberus, and Tomoregulin-1, which can interfere with Nodal receptor binding.<ref name="Branford"/><ref name="Shen"/>
| summary_text = The protein encoded by this gene is a member of the TGF-beta superfamily. Studies of the mouse counterpart suggested that this gene may be essential for mesoderm formation and subsequent organization of axial structures in early embryonic development.<ref name="entrez">{{cite web | title = Entrez Gene: NODAL nodal homolog (mouse)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4838| accessdate = }}</ref>
 
}}
== Species specific Nodal Ligands ==
 
Nodal is a widely distributed [[cytokine]].<ref>{{cite book|authors=Chen, Hsu-Hsin & Geijsen, Neils|chapter=Signaling germline commitment|editors=Simón, Carlos & Pellicer, Antonio|title=Stem cells in human reproduction: basic science and therapeutic potential|publisher=CRC Press|year=2006|isbn=978-0-415-39777-3|page=74|url=https://books.google.com/books?id=rShYiEGhvt4C&pg=PA74}}</ref> The presence of Nodal is not limited to [[vertebrates]], it is also known to be conserved in other [[deuterostome]]s ([[cephalochordate]]s, [[tunicate]]s and [[echinoderm]]s) and [[protostome]]s such as snails, but interestingly neither the nematode ''[[Caenorhabditis elegans|C. elegans]]'' (another protosome) nor the fruit fly ''Drosophila'' (an arthropod) have a copy of nodal.<ref name="Chea_2005">{{cite journal |vauthors=Chea HK, Wright CV, Swalla BJ | title = Nodal signaling and the evolution of deuterostome gastrulation | journal = Dev. Dyn. | volume = 234 | issue = 2 | pages = 269–78 |date=October 2005 | pmid = 16127715 | doi = 10.1002/dvdy.20549 | url = | issn = }}</ref><ref name="Schier_2009">{{cite journal | author = Schier AF | title = Nodal morphogens | journal = Cold Spring Harb Perspect Biol | volume = 1 | issue = 5 | pages = a003459 |date=November 2009 | pmid = 20066122 | pmc = 2773646 | doi = 10.1101/cshperspect.a003459 | url = | issn = }}</ref> 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.<ref name="Baker_2008">{{cite journal |vauthors=Baker K, Holtzman NG, Burdine RD | title = Direct and indirect roles for Nodal signaling in two axis conversions during asymmetric morphogenesis of the zebrafish heart | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 37 | pages = 13924–9 |date=September 2008 | pmid = 18784369 | pmc = 2544555 | doi = 10.1073/pnas.0802159105 | url = | issn = }}</ref> 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.<ref name="Luxardi_2010">{{cite journal |vauthors=Luxardi G, Marchal L, Thomé V, Kodjabachian L | title = Distinct Xenopus Nodal ligands sequentially induce mesendoderm and control gastrulation movements in parallel to the Wnt/PCP pathway | journal = Development | volume = 137 | issue = 3 | pages = 417–26 |date=February 2010 | pmid = 20056679 | doi = 10.1242/dev.039735 | url = | issn = }}</ref> 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.<ref name="Shen"/> In chick development, Nodal is expressed in [[Koller's sickle]].<ref>{{cite book|last=Schnell|first=Santiago|title=Multiscale Modeling of Developmental Systems|url=https://books.google.com/books?id=wc6irQKViJcC&pg=PA167&lpg=PA167&dq=analogous+system+to+koller's+sickle&source=bl&ots=w18_v5T8CM&sig=ymbwS_F0OfEFzYtRkIuyBaxQcbs&hl=en&sa=X&ei=6EijUom5DKG2sAT1iICAAQ&ved=0CCsQ6AEwAA#v=onepage&q=analogous%20system%20to%20koller's%20sickle&f=false|accessdate=7 December 2013}}</ref>  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]].<ref name="Conlon_1994">{{cite journal |vauthors=Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, Robertson EJ | title = A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse | journal = Development | volume = 120 | issue = 7 | pages = 1919–28 |date=July 1994 | pmid = 7924997 | doi = | url = | issn = }}</ref><ref name="Zhou_1993">{{cite journal |vauthors=Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR | title = Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation | journal = Nature | volume = 361 | issue = 6412 | pages = 543–7 |date=February 1993 | pmid = 8429908 | doi = 10.1038/361543a0 | url = | issn = }}</ref><ref name="pmid11485994">{{cite journal  |vauthors=Reissmann E, Jörnvall H, Blokzijl A, etal |title=The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development |journal=Genes Dev. |volume=15 |issue=15 |pages=2010–22 |date=August 2001 |pmid=11485994 |pmc=312747 |doi=10.1101/gad.201801 |url= }}</ref>
 
Compared to [[mesoderm]] specification, [[endoderm]] specification requires a higher expression of Nodal. Here, Nodal stimulates mixer homeoproteins, which can interact with [[SMAD (protein)|SMAD]]s in order to up-regulate [[endoderm]] specific genes and repress [[mesoderm]] specific genes.<ref name="Shen"/>
 
Left-right (LR) asymmetry of visceral organs in [[vertebrate]]s 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.<ref name="Strizzi"/><ref name="Shen"/> It is highly conserved among deuterostomes.<ref name="pmid11836504">{{cite journal |vauthors=Hamada H, Meno C, Watanabe D, Saijoh Y | title = Establishment of vertebrate left-right asymmetry | journal = Nat. Rev. Genet. | volume = 3 | issue = 2 | pages = 103–13 |date=February 2002 | pmid = 11836504 | doi = 10.1038/nrg732 | url = | issn = }}</ref><ref name="pmid19098895">{{cite journal |vauthors=Grande C, Patel NH | title = Nodal signalling is involved in left-right asymmetry in snails | journal = Nature | volume = 457 | issue = 7232 | pages = 1007–11 |date=February 2009 | pmid = 19098895 | pmc = 2661027 | doi = 10.1038/nature07603 | url = | issn = }}</ref> An [[ortholog]] of Nodal was recently found in [[snail]]s and was shown to be involved in left-right asymmetry as well.<ref name="pmid19098895"/>
 
In order to enable anterior neural tissue development, Nodal signaling needs to be repressed after inducing mesendoderm and LR symmetry.<ref name="Shen"/><ref name="Schier"/>
 
Recent research on mouse and human [[embryonic stem cell]]s (hESCs) indicates that Nodal seems to be involved in the maintenance of [[stem cell]] self-renewal and [[pluripotency|pluripotent]] potentials.<ref name="Strizzi"/><ref name="Shen"/><ref name="Chngz">{{cite journal |vauthors=Chng Z, Vallier L, Pedersen R | title = Activin/ nodal signaling and pluripotency | journal = Vitamins and hormones | volume = 85 | issue = | pages = 38–58 | year = 2011 | month = | pmid = 21353875 | pmc = | doi = 10.1016/B978-0-12-385961-7.00003-2 }}</ref><ref name="Fei">{{cite journal |vauthors=Fei T, Chen YG | title = Regulation of embryonic stem cell self-renewal and differentiation by TGF-beta family signaling | journal = Science China Life Sciences | volume = 53 | issue = 4 | pages = 497–503 |date=Apr 2010 | pmid = 20596917 | pmc =  | doi = 10.1007/s11427-010-0096-2 }}</ref> Thus, overexpression of Nodal in hESCs lead to the repression of cell differentiation.<ref name="Shen"/> On the contrary, inhibition of Nodal and Activin signaling enabled the differentiation of hESCs.<ref name="Strizzi"/>


==References==
==References==
{{reflist|2}}
{{reflist|35em}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
*{{cite journal  |vauthors=Postovit LM, Seftor EA, Seftor RE, Hendrix MJ |title=Targeting Nodal in malignant melanoma cells. |journal=Expert Opin. Ther. Targets |volume=11 |issue= 4 |pages= 497–505 |year= 2007 |pmid= 17373879 |doi= 10.1517/14728222.11.4.497 }}
| citations =
*{{cite journal   |vauthors=Yan YT, Liu JJ, Luo Y, etal |title=Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. |journal=Mol. Cell. Biol. |volume=22 |issue= 13 |pages= 4439–49 |year= 2002 |pmid= 12052855 |doi=10.1128/MCB.22.13.4439-4449.2002 |pmc=133918}}
*{{cite journal  | author=Postovit LM, Seftor EA, Seftor RE, Hendrix MJ |title=Targeting Nodal in malignant melanoma cells. |journal=Expert Opin. Ther. Targets |volume=11 |issue= 4 |pages= 497-505 |year= 2007 |pmid= 17373879 |doi= 10.1517/14728222.11.4.497 }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 |pmc=139241}}
*{{cite journal | author=Zhou X, Sasaki H, Lowe L, ''et al.'' |title=Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation. |journal=Nature |volume=361 |issue= 6412 |pages= 543-7 |year= 1993 |pmid= 8429908 |doi= 10.1038/361543a0 }}
*{{cite journal   |vauthors=Roberts HJ, Hu S, Qiu Q, etal |title=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. |journal=Biol. Reprod. |volume=68 |issue= 5 |pages= 1719–26 |year= 2003 |pmid= 12606401 |doi= 10.1095/biolreprod.102.013045 }}
*{{cite journal  | author=Gebbia M, Ferrero GB, Pilia G, ''et al.'' |title=X-linked situs abnormalities result from mutations in ZIC3. |journal=Nat. Genet. |volume=17 |issue= 3 |pages= 305-8 |year= 1997 |pmid= 9354794 |doi= 10.1038/ng1197-305 }}
*{{cite journal   |vauthors=Munir S, Xu G, Wu Y, etal |title=Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. |journal=J. Biol. Chem. |volume=279 |issue= 30 |pages= 31277–86 |year= 2004 |pmid= 15150278 |doi= 10.1074/jbc.M400641200 }}
*{{cite journal  | author=Yan YT, Liu JJ, Luo Y, ''et al.'' |title=Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. |journal=Mol. Cell. Biol. |volume=22 |issue= 13 |pages= 4439-49 |year= 2002 |pmid= 12052855 |doi= }}
*{{cite journal   |vauthors=Haffner C, Frauli M, Topp S, etal |title=Nicalin and its binding partner Nomo are novel Nodal signaling antagonists. |journal=EMBO J. |volume=23 |issue= 15 |pages= 3041–50 |year= 2005 |pmid= 15257293 |doi= 10.1038/sj.emboj.7600307 |pmc=514924}}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Besser D |title=Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. |journal=J. Biol. Chem. |volume=279 |issue= 43 |pages= 45076–84 |year= 2004 |pmid= 15308665 |doi= 10.1074/jbc.M404979200 }}
*{{cite journal | author=Roberts HJ, Hu S, Qiu Q, ''et al.'' |title=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. |journal=Biol. Reprod. |volume=68 |issue= 5 |pages= 1719-26 |year= 2003 |pmid= 12606401 |doi= 10.1095/biolreprod.102.013045 }}
*{{cite journal   |vauthors=Bamforth SD, Bragança J, Farthing CR, etal |title=Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. |journal=Nat. Genet. |volume=36 |issue= 11 |pages= 1189–96 |year= 2004 |pmid= 15475956 |doi= 10.1038/ng1446 }}
*{{cite journal | author=Munir S, Xu G, Wu Y, ''et al.'' |title=Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. |journal=J. Biol. Chem. |volume=279 |issue= 30 |pages= 31277-86 |year= 2004 |pmid= 15150278 |doi= 10.1074/jbc.M400641200 }}
*{{cite journal   |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 |pmc=528928}}
*{{cite journal | author=Haffner C, Frauli M, Topp S, ''et al.'' |title=Nicalin and its binding partner Nomo are novel Nodal signaling antagonists. |journal=EMBO J. |volume=23 |issue= 15 |pages= 3041-50 |year= 2005 |pmid= 15257293 |doi= 10.1038/sj.emboj.7600307 }}
*{{cite journal  |vauthors=Vallier L, Reynolds D, Pedersen RA |title=Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. |journal=Dev. Biol. |volume=275 |issue= 2 |pages= 403–21 |year= 2005 |pmid= 15501227 |doi= 10.1016/j.ydbio.2004.08.031 }}
*{{cite journal  | author=Besser D |title=Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. |journal=J. Biol. Chem. |volume=279 |issue= 43 |pages= 45076-84 |year= 2004 |pmid= 15308665 |doi= 10.1074/jbc.M404979200 }}
*{{cite journal   |vauthors=Hart AH, Willson TA, Wong M, etal |title=Transcriptional regulation of the homeobox gene Mixl1 by TGF-beta and FoxH1. |journal=Biochem. Biophys. Res. Commun. |volume=333 |issue= 4 |pages= 1361–9 |year= 2005 |pmid= 15982639 |doi= 10.1016/j.bbrc.2005.06.044 }}
*{{cite journal | author=Bamforth SD, Bragança J, Farthing CR, ''et al.'' |title=Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. |journal=Nat. Genet. |volume=36 |issue= 11 |pages= 1189-96 |year= 2004 |pmid= 15475956 |doi= 10.1038/ng1446 }}
*{{cite journal  |vauthors=Vallier L, Alexander M, Pedersen RA |title=Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. |journal=J. Cell Sci. |volume=118 |issue= Pt 19 |pages= 4495–509 |year= 2006 |pmid= 16179608 |doi= 10.1242/jcs.02553 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal |vauthors=Strizzi L, Postovit LM, Margaryan NV, Seftor EA, Abbott DE, Seftor RE, Salomon DS, Hendrix MJ | title= Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression | journal= Breast disease | volume= 29 | issue= | pages= 91–103 | year= 2008 | month= | pmid= 19029628 | pmc= 3175751 | doi= }}
*{{cite journal  | author=Vallier L, Reynolds D, Pedersen RA |title=Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. |journal=Dev. Biol. |volume=275 |issue= 2 |pages= 403-21 |year= 2005 |pmid= 15501227 |doi= 10.1016/j.ydbio.2004.08.031 }}
*{{cite journal |vauthors=Branford WW, Yost HJ | title= Nodal signaling: CrypticLefty mechanism of antagonism decoded | journal= Current Biology | volume= 14 | issue= 9 | pages= R341-3 |date=May 2004 | pmid= 15120085 | pmc=  | doi= 10.1016/j.cub.2004.04.020 }}
*{{cite journal | author=Hart AH, Willson TA, Wong M, ''et al.'' |title=Transcriptional regulation of the homeobox gene Mixl1 by TGF-beta and FoxH1. |journal=Biochem. Biophys. Res. Commun. |volume=333 |issue= 4 |pages= 1361-9 |year= 2005 |pmid= 15982639 |doi= 10.1016/j.bbrc.2005.06.044 }}
*{{cite journal | author= Shen MM | title= Nodal Signaling: development and regulation | journal= Development | volume= 134 | issue= 6 | pages= 1023–34 |date=March 2007 | pmid= 17287255 | pmc=  | doi= 10.1242/dev.000166 }}
*{{cite journal  | author=Vallier L, Alexander M, Pedersen RA |title=Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. |journal=J. Cell. Sci. |volume=118 |issue= Pt 19 |pages= 4495-509 |year= 2006 |pmid= 16179608 |doi= 10.1242/jcs.02553 }}
*{{cite journal | author= Schier AF | title= Nodal Signaling in vertebrate development | journal= Annual Review of Cell and Developmental Biology | volume= 19 | issue=  | pages= 589–621 |date=Aug 2003 | pmid= 14570583 | pmc=  | doi= 10.1146/annurev.cellbio.19.041603.094522 }}
}}
*{{cite journal |vauthors=Chng Z, Vallier L, Pedersen R | title= Activin/ nodal signaling and pluripotency | journal= Vitamins and hormones | volume= 85 | issue= | pages= 38–58 | year= 2011 | month= | pmid= 21353875 | pmc= | doi= 10.1016/B978-0-12-385961-7.00003-2 }}
*{{cite journal |vauthors=Fei T, Chen YG | title= Regulation of embryonic stem cell self-renewal and differentiation by TGF-beta family signaling | journal= Science China Life Sciences | volume= 53 | issue= 4 | pages= 497–503 |date=Apr 2010 | pmid= 20596917 | pmc=  | doi= 10.1007/s11427-010-0096-2 }}
{{refend}}
{{refend}}


{{protein-stub}}
==External links==
{{WikiDoc Sources}}
* {{MeshName|nodal+protein}}
* [http://pandasthumb.org/archives/2009/04/snails-have-nod.html Snails have nodal!]
 
{{TGF beta signaling}}
{{TGFβ receptor superfamily modulators}}
 
[[Category:Developmental genes and proteins]]
[[Category:TGFβ domain]]

Revision as of 20:27, 8 November 2017

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Orthologs
SpeciesHumanMouse
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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]

Signaling

Main article: Nodal 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 interestingly 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 recently found in snails and was shown to be involved in left-right asymmetry as well.[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. ↑ 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.

Further reading

External links

Retrieved from "https://www.wikidoc.org/index.php?title=NODAL&oldid=1414383"