NodalSignalingPathwayfinaledition

1、Nodal Signaling Pathway -Reporter Liu Jingwen From Group 45/18/2022Introduction To Nodal Signaling PathwayThe Nodal gene was discovered in genetic studies in mouse . Retroviral mutagenesis led to the isolation of an insert that affected gastrulation and discovered a novel member of the TGF-beta fami

2、ly of signaling m-olecule-Nodal . The finding of Nodal was of significance a signal essential for mammalian gastrulation the long-sought vertebrate mesoderm inducer Implicated in left-right asymmetry Late, Nodal was also found in other vertebrates,like zebrafish,Xenopus. 5/18/2022Introduction To Nod

3、al Signaling PathwayNodal signaling pathway belong to TGF-beta superfamily, but several proteins have specific roles in Nodal signaling pathway, and Nodal signaling pathway isrestricated to chordates.Nodal signaling pathway plays an important role in early embryogenesis ,espec-Ially in vertebrate bo

4、dy plan (L-R , posterior-anterior) .5/18/20225/18/2022The Other Member of Nodal Signaling PathwayNodal signaling is activated by the interaction of Nodals with receptors(ActRIIB,ALK4) and EGF-CFC coreceptors, and it is inhibited by Leftys and Cerberus . Nodal signaling is transmitted intracellularly

5、 by phosphorylation of Smad2 and its association with Smad4 and transcription factor (FoxH1,Mixer) that determine which genes are regulated by P-Smad2.5/18/2022NodalGeneSpeciesPhenotypes and roleCyclopsZebrafishReduced prechordal mesoderm, lack of floor plate, can act a short range.SquintZebrafishDe

6、fects in axial mesoderm ,acts as a long-range morphogenNodalMouseAnterior-posterior axis not established ;no anterior visceral endoderm ;reduced mesendodermXnr1,2,4,5,6FrogMesendoderm induction and L-R development5/18/2022NodalIn contrast to the Wnt or Notch signaling systems,Nodal have not been fou

7、nd in Drosophila or C.elegans.Nodal have a more selective role during vertebrate development.(It suggest the Nodal has been coupled to vertebrate evolution . )Nodals have similar biochemical activities. For instance, heterologousNodals can act as mesoderm inducer in Xenopus and zebrafish , similar t

8、o the endogenous signals.Nodals can also heterodimerize with other TGF-beta ligands , leading to cooperative interactions or to mutual inhibition.5/18/2022Receptor and CoreceptorNodals act via the receptors ActRIB(ALK4), ActRIIA, and ActRIIB.Additional receptors are likely to be involved in mediatin

9、g Nodal sign-aling.The use of multiple receptors could diversify the output of Nodal sign-aling.5/18/20225/18/2022Receptor and CoreceptorMembers of EGF-CFC family are extracellular proteins.It is now firmly established that EGF-CFC proteins are important co-mponents of the Nodal signaling pathway ,

10、most likely by acting as co-receptors for Nodal ligandsThe coreceptors might change the conformation of receptors to allow interactions with Nodals. The EGF-CFC proteins might also activate non-TGF-beta signaling pa- thway.It might allow the cross-talk of Nodal signaling with other sig- naling pathw

11、ays.5/18/2022Extracellular InhibitorsLefty Leftys molecules are divergent members of the TGF-beta family. Unlike other TGF-beta-related factors , Leftys lack a cysteine re- sidue required for formation of covalently linked dimers and ap- pear to be monomeric upon expression in Xenopus oocytes. Lefty

12、s proteins act as antagonists of the Nodal signaling pathway. For example, overexpression of Leftys in zebrafish induces pheno- types strongly resembling cyclops;squint double mutants .5/18/2022Mol.cell 4:287-985/18/2022Extracellular Inhibitors Cerberus A truncated form of Cerberus , Cer-s , have be

13、en found to specifically block Nodal by direct binding to the ligand . Overexpression of Cer-s leads to phenotypes resembling the loss of Nodal signaling in zebrafish and mouse , incliding defects in mesendoderm induction. 5/18/2022TFs and Downstream of Nodal Signaling Similar to other TGF-beta sign

14、als , Nodal signaling results in phos- phorylation of regulatory Smads and their association with Smads4 , translocation into the nucleus , and regulation of downstream genes by interaction with specific TFs . FoxH1 is the most thoroughly studied TF associated with P-smad2 to regulate specific downs

15、tream targets of Nodal signaling . Mixer might also a factor that regulate Nodal signaling. p53 might also contribute to Nodal signaling and act as coactivator of of genes regulated by P-smad2 in Xenopus embryos .5/18/2022TFs and Downstream of Nodal Signaling Autoregulatory interactions modulate the

16、 expression of components of the Nodal signaling pathway . 5/18/20225/18/20225/18/2022L-R Axis Formation Members of the Nodal gene family in each vertebrate species are specifically expressed in the left ,but not right . The presence of Nodal signals in the lateral plate mesoderm has thus been propo

17、- sed to determine “l(fā)eft-sidedness” , and absence of Nodal to det- ermine “right-sidedness” . Ectopic expression of Nodal on the ri- ght side can perturb the asymmetry of internal organs .5/18/2022L-R Axis Formation Signaling by components of the Nodal signaling pathway is not re- quired for the asy

18、mmetric development of organs per se , but it controls the laterality of asymmetry . For example , in the zebrafish diencephalon , the parapineal organ is normally located on the left . In the absence of Nodal signaling , the parapineal is still located asymmetrically , but in approximately half of

19、the mutants it is located on the right . 5/18/2022Neuron, Vol. 28, 399409, November, 20005/18/2022Perspective Highly dynamic tissues that undergo widespread remodeling events, such as the mammary gland and the cycling endometrium also express this morphogen. In addition, several studies have demonst

20、rated that Nodal is expressed in highly invasive cancers including melanoma, glioma, pancreatic, endometrial and breast cancer and that in each of these cases it promotes a highly invasive phenotype . It suggest that Nodal signaling pathway can be a target for cancer therapy .5/18/20225/18/2022Semin

21、ars in cancer biology . 2014 . 1-115/18/2022Seminars in cancer biology . 2014 . 1-11References1 Alexander F. Schier .Nodal signaling in vertebrate development .Annu.Rev. Cell Dev.Biol.2003.19:589-6212 Alexander F. Schier & Micheal M Shen . Nodal signaling in vertebrate develop- ment .Nature 2000.403:385-3893 Concha ML et al. A nodal signaling pathway regulates the laterality of neuro- anatomical asymmetries in zebrafish forebrain . Neuron 28:399-4094 Meno C et al. Mouse Lefty2 and zebrafish activin are feedback inhibitors of nodal signaling during verte