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0890-936917102003May15Genes & developmentGenes DevNotch signaling regulates left-right asymmetry determination by inducing Nodal expression.120712121207-12Generation of left-right asymmetry is an integral part of the establishment of the vertebrate body plan. Here we show that the Notch signaling pathway plays a primary role in the establishment of left-right asymmetry in mice by directly regulating expression of the Nodal gene. Embryos mutant for the Notch ligand Dll1 or doubly mutant for the Notch1 and Notch2 receptors exhibit multiple defects in left-right asymmetry. Analysis of the enhancer regulating node-specific Nodal expression revealed the presence of binding sites for the RBP-J protein, the primary transcriptional mediator of Notch signaling. Mutation of these sites destroyed the ability of this enhancer to direct node-specific gene expression in transgenic mice. Our results demonstrate that Dll1-mediated Notch signaling is essential for generation of left-right asymmetry, and that the Notch pathway acts upstream of Nodal expression during left-right asymmetry determination in mice.KrebsLuke TLTThe Jackson Laboratory, Bar Harbor, Maine 04609, USA.IwaiNaomiNNonakaShigenoriSWelshIan CICLanYuYJiangRulangRSaijohYukioYO'BrienTimothy PTPHamadaHiroshiHGridleyThomasTengHD36434HDNICHD NIH HHSUnited StatesNS36437NSNINDS NIH HHSUnited StatesP30 CA034196CANCI NIH HHSUnited StatesHD41066HDNICHD NIH HHSUnited StatesR01 HD041066HDNICHD NIH HHSUnited StatesR01 NS036437NSNINDS NIH HHSUnited StatesCA34196CANCI NIH HHSUnited StatesJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.20030502
United StatesGenes Dev87116600890-93690Intracellular Signaling Peptides and Proteins0Left-Right Determination Factors0Membrane Proteins0Nodal Protein0Nodal protein, mouse0Receptors, Notch0Transforming Growth Factor beta0delta proteinIMAnimalsBinding SitesBody PatterningphysiologyCiliageneticsmetabolismEnhancer Elements, GeneticGene Expression Regulation, DevelopmentalphysiologyIntracellular Signaling Peptides and ProteinsLeft-Right Determination FactorsMembrane ProteinsmetabolismphysiologyMiceMutationNodal ProteinReceptors, NotchSignal TransductionphysiologyTransforming Growth Factor betageneticsmetabolism200356502003620502003565020031115ppublish12730124PMC19605910.1101/gad.1084703U-10847RspAdachi H, Saijoh Y, Mochida K, Ohishi S, Hashiguchi H, Hirao A, Hamada H. Determination of left/right asymmetric expression of nodal by a left side-specific enhancer with sequence similarity to a lefty-2 enhancer. 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