Gene Symbol: Lefty2
Description: left-right determination factor 2
Alias: 6030463A22Rik, Ebaf, Lefta, Leftb, lefty-2, lefty-B, left-right determination factor 2, endometrial bleeding associated factor, left-right determination factor B, left-right determination, factor A
Species: mouse
Products:     Lefty2

Top Publications

  1. Meno C, Ito Y, Saijoh Y, Matsuda Y, Tashiro K, Kuhara S, et al. Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells. 1997;2:513-24 pubmed
    ..Lefty-1 and Lefty-2 possess direct neuralizing activity in Xenopus embryos, resembling the activities of BMP antagonists. ..
  2. Meno C, Shimono A, Saijoh Y, Yashiro K, Mochida K, Ohishi S, et al. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell. 1998;94:287-97 pubmed
    ..These observations suggest that the role of lefty-1 is to restrict the expression of lefty-2 and nodal to the left side, and that lefty-2 or nodal encodes a signal for "leftness." ..
  3. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell. 1998;95:829-37 pubmed
  4. Beck S, Le Good J, Guzman M, Ben Haim N, Roy K, Beermann F, et al. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nat Cell Biol. 2002;4:981-5 pubmed
    ..A lack of Spc1 and Spc4 affects both pathways because these proteases also stimulate induction of Bmp4. ..
  5. Constam D, Robertson E. Tissue-specific requirements for the proprotein convertase furin/SPC1 during embryonic turning and heart looping. Development. 2000;127:245-54 pubmed
    ..Overall, we conclude that Furin activity is essential in both extraembryonic and precardiac mesoderm, and in definitive endoderm derivatives. ..
  6. Camus A, Perea Gomez A, Moreau A, Collignon J. Absence of Nodal signaling promotes precocious neural differentiation in the mouse embryo. Dev Biol. 2006;295:743-55 pubmed
  7. Ben Haim N, Lu C, Guzman Ayala M, Pescatore L, Mesnard D, Bischofberger M, et al. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev Cell. 2006;11:313-23 pubmed
    ..Based on mathematical modeling, we discuss how these sequential loops control cell fate. ..
  8. Nakamura T, Mine N, Nakaguchi E, Mochizuki A, Yamamoto M, Yashiro K, et al. Generation of robust left-right asymmetry in the mouse embryo requires a self-enhancement and lateral-inhibition system. Dev Cell. 2006;11:495-504 pubmed
    ..Nodal and Lefty are deployed as a SELI system required to amplify this initial bias and convert it into robust asymmetry. ..
  9. Perea Gomez A, Vella F, Shawlot W, Oulad Abdelghani M, Chazaud C, Meno C, et al. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev Cell. 2002;3:745-56 pubmed
    ..Both antagonists are also required for proper patterning of the primitive streak. ..

More Information


  1. Saijoh Y, Oki S, Ohishi S, Hamada H. Left-right patterning of the mouse lateral plate requires nodal produced in the node. Dev Biol. 2003;256:160-72 pubmed
    ..Conversely, ectopic expression of the Nodal inhibitor Lefty2 in the node of Nodal(neo/+) embryos resulted in a phenotype similar to that of the Nodal(neo/neo) mutant...
  2. Brennan J, Lu C, Norris D, Rodriguez T, Beddington R, Robertson E. Nodal signalling in the epiblast patterns the early mouse embryo. Nature. 2001;411:965-9 pubmed
    ..Our experiments show that proximal-distal and subsequent anterior-posterior polarity of the pregastrulation embryo result from reciprocal cell-cell interactions between the epiblast and the two extra-embryonic tissues. ..
  3. Yamamoto M, Meno C, Sakai Y, Shiratori H, Mochida K, Ikawa Y, et al. The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes Dev. 2001;15:1242-56 pubmed
    ..These results indicate that a Nodal-FoxH1 signaling pathway plays a central role in A-P patterning and node formation in the mouse. ..
  4. Lowe L, Yamada S, Kuehn M. Genetic dissection of nodal function in patterning the mouse embryo. Development. 2001;128:1831-43 pubmed
    ..We find that nodal signaling is required for correct positioning of the anteroposterior axis, normal anterior and midline patterning, and the left-right asymmetric development of the heart, vasculature, lungs and stomach. ..
  5. Constam D, Robertson E. SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Genes Dev. 2000;14:1146-55 pubmed
    ..analysis during early somite stages indicates that spc4 is genetically upstream of nodal, pitx2, lefty1, and lefty2 and perhaps maintains the balance between Nodal and BMP signaling in the lateral plate that is critical for L/R ..
  6. Saijoh Y, Adachi H, Sakuma R, Yeo C, Yashiro K, Watanabe M, et al. Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol Cell. 2000;5:35-47 pubmed
    The left-right (L-R) asymmetric expression of lefty2 and nodal is controlled by a left side-specific enhancer (ASE)...
  7. Maisonneuve C, Guilleret I, Vick P, Weber T, Andre P, Beyer T, et al. Bicaudal C, a novel regulator of Dvl signaling abutting RNA-processing bodies, controls cilia orientation and leftward flow. Development. 2009;136:3019-30 pubmed publisher
    ..These results suggest a model whereby BicC links the orientation of cilia with PCP, possibly by regulating RNA silencing in P-bodies. ..
  8. Norris D, Brennan J, Bikoff E, Robertson E. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development. 2002;129:3455-68 pubmed
    ..However loss of the ASE disrupts Lefty2 (Leftb) expression and causes delayed Pitx2 expression leading to late onset, relatively minor LR patterning ..
  9. Brennan J, Norris D, Robertson E. Nodal activity in the node governs left-right asymmetry. Genes Dev. 2002;16:2339-44 pubmed
    ..Our findings confirm that the mouse node is instrumental in initiating left-right axis specification and identify Nodal as the key morphogen regulating this process. ..
  10. Dufort D, Schwartz L, Harpal K, Rossant J. The transcription factor HNF3beta is required in visceral endoderm for normal primitive streak morphogenesis. Development. 1998;125:3015-25 pubmed
    ..We show that such mutant embryos lack foregut and midgut endoderm. In addition, left-right asymmetry is affected in the mutant embryos. ..
  11. Robertson E, Norris D, Brennan J, Bikoff E. Control of early anterior-posterior patterning in the mouse embryo by TGF-beta signalling. Philos Trans R Soc Lond B Biol Sci. 2003;358:1351-7; discussion 1357 pubmed
  12. Vierkotten J, Dildrop R, Peters T, Wang B, Ruther U. Ftm is a novel basal body protein of cilia involved in Shh signalling. Development. 2007;134:2569-77 pubmed
    ..Furthermore, the absence of Ftm in arthropods underlines the divergence between vertebrate and Drosophila Hh pathways...
  13. Halstead A, Wright C. Disrupting Foxh1-Groucho interaction reveals robustness of nodal-based embryonic patterning. Mech Dev. 2015;136:155-65 pubmed publisher
    ..transcriptional activator for genes targeted by Nodal signaling including Nodal itself, the feedback inhibitor Lefty2, and the positive transcriptional effector Pitx2...
  14. Khoueiry R, Sohni A, Thienpont B, Luo X, Velde J, Bartoccetti M, et al. Lineage-specific functions of TET1 in the postimplantation mouse embryo. Nat Genet. 2017;49:1061-1072 pubmed publisher
    ..Collectively, our study highlights an interplay between the catalytic and non-catalytic activities of TET1 that is essential for normal development. ..
  15. Takeda S, Yonekawa Y, Tanaka Y, Okada Y, Nonaka S, Hirokawa N. Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A-/- mice analysis. J Cell Biol. 1999;145:825-36 pubmed
    ..These results suggest that KIF3A might be involved in mesodermal patterning and in turn neurogenesis. ..
  16. Mavrakis K, Andrew R, Lee K, Petropoulou C, Dixon J, Navaratnam N, et al. Arkadia enhances Nodal/TGF-beta signaling by coupling phospho-Smad2/3 activity and turnover. PLoS Biol. 2007;5:e67 pubmed
    ..This mechanism can account for achieving efficient and maximum Nodal signaling during embryogenesis and for rapid resetting of target gene promoters allowing cells to respond to dynamic changes in extracellular signals. ..
  17. Field S, Riley K, Grimes D, Hilton H, Simon M, Powles Glover N, et al. Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2. Development. 2011;138:1131-42 pubmed publisher
    ..Together with co-expression in the node, these data argue that Pkd1l1 is the elusive Pkd2 binding partner required for L-R patterning and support the two-cilia hypothesis. ..
  18. Cinelli P, Casanova E, Uhlig S, Lochmatter P, Matsuda T, Yokota T, et al. Expression profiling in transgenic FVB/N embryonic stem cells overexpressing STAT3. BMC Dev Biol. 2008;8:57 pubmed publisher
    ..The expression of four of the up-regulated genes (Hexokinase II, Lefty2, Pramel7, PP1rs15B) was shown to be restricted to the inner cell mass (ICM) of the blastocysts...
  19. Oki S, Hashimoto R, Okui Y, Shen M, Mekada E, Otani H, et al. Sulfated glycosaminoglycans are necessary for Nodal signal transmission from the node to the left lateral plate in the mouse embryo. Development. 2007;134:3893-904 pubmed
    ..Inhibition of sulfated GAG biosynthesis prevents Nodal expression in the LPM. These data suggest that Nodal produced at the node might travel directly to the LPM via interaction with sulfated GAGs. ..
  20. Cota C, Bagher P, Pelc P, Smith C, Bodner C, Gunn T. Mice with mutations in Mahogunin ring finger-1 (Mgrn1) exhibit abnormal patterning of the left-right axis. Dev Dyn. 2006;235:3438-47 pubmed
    ..Our work identifies a novel role for MGRN1 in embryonic patterning and suggests that the ubiquitination of MGRN1 target genes is essential for the proper establishment and/or maintenance of the LR axis. ..
  21. Kimura C, Yoshinaga K, Tian E, Suzuki M, Aizawa S, Matsuo I. Visceral endoderm mediates forebrain development by suppressing posteriorizing signals. Dev Biol. 2000;225:304-21 pubmed
    ..These results suggest that distal visceral endoderm cells move to the future anterior side to generate a prospective forebrain territory indirectly, by preventing posteriorizing signals. ..
  22. Miura S, Davis S, Klingensmith J, Mishina Y. BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites. Development. 2006;133:3767-75 pubmed
    ..This suggests that BMP and FGF signaling function antagonistically during paraxial mesoderm development. ..
  23. Kelly O, Pinson K, Skarnes W. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development. 2004;131:2803-15 pubmed
    ..The effect of reducing, but not eliminating, Wnt signaling in Lrp5(+/-);Lrp6(-/-) mutant embryos provides important insight into the interplay between Wnt, Fgf and Nodal signals in patterning the early mouse embryo. ..
  24. Nowotschin S, Costello I, Piliszek A, Kwon G, Mao C, Klein W, et al. The T-box transcription factor Eomesodermin is essential for AVE induction in the mouse embryo. Genes Dev. 2013;27:997-1002 pubmed publisher
    ..Thus, Eomes function in the visceral endoderm (VE) initiates an instructive transcriptional program controlling AP identity. ..
  25. Hoover A, Wynkoop A, Zeng H, Jia J, Niswander L, Liu A. C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development. 2008;135:4049-58 pubmed publisher
    ..Interestingly, the human ortholog for this gene lies in proximity to the critical regions of Meckel-Gruber syndrome 2 (MKS2) and Joubert syndrome 2 (JBTS2), making it a potential candidate for these two human genetic disorders. ..
  26. Meno C, Takeuchi J, Sakuma R, Koshiba Takeuchi K, Ohishi S, Saijoh Y, et al. Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev Cell. 2001;1:127-38 pubmed
    The role of Lefty2 in left-right patterning was investigated by analysis of mutant mice that lack asymmetric expression of lefty2. These animals exhibited various situs defects including left isomerism...
  27. Zhang X, Ramalho Santos M, McMahon A. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell. 2001;105:781-92 pubmed
    ..Further, we demonstrate an absolute requirement for Hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis.[Dedicated to Rosa Beddington, a pioneer in mammalian embryology]. ..
  28. Krebs L, Iwai N, Nonaka S, Welsh I, Lan Y, Jiang R, et al. Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev. 2003;17:1207-12 pubmed
    ..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. ..
  29. Niederreither K, Vermot J, Messaddeq N, Schuhbaur B, Chambon P, Dolle P. Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development. 2001;128:1019-31 pubmed
    ..However, cardiac neural crest cells cannot be properly rescued in Raldh2(-/- )embryos, leading to outflow tract septation defects. ..
  30. Zhang M, Bolfing M, Knowles H, Karnes H, Hackett B. Foxj1 regulates asymmetric gene expression during left-right axis patterning in mice. Biochem Biophys Res Commun. 2004;324:1413-20 pubmed
    ..Foxj1 thus acts early in left-right axis patterning and regulates asymmetric gene expression. This regulation does not appear to be the result of a direct interaction between Foxj1 and the genes examined. ..
  31. Faisst A, Alvarez Bolado G, Treichel D, Gruss P. Rotatin is a novel gene required for axial rotation and left-right specification in mouse embryos. Mech Dev. 2002;113:15-28 pubmed
    ..In the mouse, the lateral asymmetry of the body axis is revealed first by the asymmetric expression of nodal, lefty2 and pitx2 in the left lateral plate mesoderm of the neurulating embryo...
  32. Benz B, Nandadasa S, Takeuchi M, Grady R, Takeuchi H, LoPilato R, et al. Genetic and biochemical evidence that gastrulation defects in Pofut2 mutants result from defects in ADAMTS9 secretion. Dev Biol. 2016;416:111-122 pubmed publisher
    ..In the future, the Pofut2 and Adamts9 knockouts will be valuable tools for understanding how local changes in the properties of the extracellular matrix influence the organization of tissues during mammalian development. ..
  33. Bonnafe E, Touka M, AitLounis A, Baas D, Barras E, Ucla C, et al. The transcription factor RFX3 directs nodal cilium development and left-right asymmetry specification. Mol Cell Biol. 2004;24:4417-27 pubmed
    ..In conclusion, RFX3 is essential for the differentiation of nodal monocilia and hence for LR body axis determination. ..
  34. Saund R, Kanai Azuma M, Kanai Y, Kim I, Lucero M, Saijoh Y. Gut endoderm is involved in the transfer of left-right asymmetry from the node to the lateral plate mesoderm in the mouse embryo. Development. 2012;139:2426-35 pubmed publisher
    ..Our findings suggest an essential role of endoderm cells in the signal transfer step from the node to the LPM, possibly using gap junction communication to establish the LR axis of the mouse...
  35. Pulina M, Hou S, Mittal A, Jülich D, Whittaker C, Holley S, et al. Essential roles of fibronectin in the development of the left-right embryonic body plan. Dev Biol. 2011;354:208-20 pubmed publisher
    ..Taken together, our studies demonstrate the requisite role for a structural ECM protein and its integrin receptor in the development of the left-right axis of asymmetry in vertebrates. ..
  36. Jokela H, Rantakari P, Lamminen T, Strauss L, Ola R, Mutka A, et al. Hydroxysteroid (17beta) dehydrogenase 7 activity is essential for fetal de novo cholesterol synthesis and for neuroectodermal survival and cardiovascular differentiation in early mouse embryos. Endocrinology. 2010;151:1884-92 pubmed publisher
    ..The septum of the atrium was also defected in the knockout mice. ..
  37. Chang H, Zwijsen A, Vogel H, Huylebroeck D, Matzuk M. Smad5 is essential for left-right asymmetry in mice. Dev Biol. 2000;219:71-8 pubmed
    ..These data suggest that Smad5 is upstream of lefty-1, nodal, and lefty-2, and as a consequence also of Pitx2, and Smad5 is essential for L-R axis determination. ..
  38. Nakaya M, Biris K, Tsukiyama T, Jaime S, Rawls J, Yamaguchi T. Wnt3a links left-right determination with segmentation and anteroposterior axis elongation. Development. 2005;132:5425-36 pubmed
    ..Thus, Wnt3a links the segmentation clock and AP axis elongation with key left-determining events, suggesting that Wnt3a is an integral component of the trunk organizer. ..
  39. Kitajima S, Takagi A, Inoue T, Saga Y. MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development. 2000;127:3215-26 pubmed
    ..These results strongly indicate that the defect in the cranial-cardiac mesoderm is cell-autonomous, whereas the defect in the paraxial mesoderm is a non-cell-autonomous secondary consequence. ..
  40. Takeuchi J, Lickert H, Bisgrove B, Sun X, Yamamoto M, Chawengsaksophak K, et al. Baf60c is a nuclear Notch signaling component required for the establishment of left-right asymmetry. Proc Natl Acad Sci U S A. 2007;104:846-51 pubmed
    ..Brg1 is also required for these processes, suggesting that BAF complexes are key components of nuclear Notch signaling. We propose a critical role for Baf60c in Notch-dependent transcription and LR asymmetry. ..
  41. Perea Gomez A, Lawson K, Rhinn M, Zakin L, Brulet P, Mazan S, et al. Otx2 is required for visceral endoderm movement and for the restriction of posterior signals in the epiblast of the mouse embryo. Development. 2001;128:753-65 pubmed
  42. Mine N, Anderson R, Klingensmith J. BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment. Development. 2008;135:2425-34 pubmed publisher
    ..These results indicate that BMP antagonism is required in both the node and LPM to facilitate L-R axis establishment in the mammalian embryo. ..
  43. Ishimura A, Chida S, Osada S. Man1, an inner nuclear membrane protein, regulates left-right axis formation by controlling nodal signaling in a node-independent manner. Dev Dyn. 2008;237:3565-76 pubmed publisher
    ..heart abnormalities and found that the left side-specific genes responsible for left-right (LR) asymmetry, Nodal, Lefty2, and Pitx2, were expressed bilaterally in the lateral plate mesoderm and that their expression was enhanced ..
  44. Yamamoto M, Mine N, Mochida K, Sakai Y, Saijoh Y, Meno C, et al. Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development. 2003;130:1795-804 pubmed
    ..The mutant mice failed to express Nodal, Lefty2 and Pitx2 on the left side during embryogenesis and exhibited right isomerism...
  45. Beckers A, Alten L, Viebahn C, Andre P, Gossler A. The mouse homeobox gene Noto regulates node morphogenesis, notochordal ciliogenesis, and left right patterning. Proc Natl Acad Sci U S A. 2007;104:15765-70 pubmed
    ..Our results establish Noto as an essential regulator of node morphogenesis and ciliogenesis in the posterior notochord, and suggest Noto acts upstream of Foxj1 and Rfx3...
  46. Miura S, Singh A, Mishina Y. Bmpr1a is required for proper migration of the AVE through regulation of Dkk1 expression in the pre-streak mouse embryo. Dev Biol. 2010;341:246-54 pubmed publisher
    ..Thus, our results suggest that BMP signaling regulates the expression patterns of Dkk1 for anterior migration of the AVE. ..
  47. Przemeck G, Heinzmann U, Beckers J, Hrabe de Angelis M. Node and midline defects are associated with left-right development in Delta1 mutant embryos. Development. 2003;130:3-13 pubmed
    ..Based on expression analysis in wild-type and mutant embryos, we suggest a model, in which Notch signalling is required for the proper differentiation of node cells and node morphology...
  48. Fujiwara T, Dehart D, Sulik K, Hogan B. Distinct requirements for extra-embryonic and embryonic bone morphogenetic protein 4 in the formation of the node and primitive streak and coordination of left-right asymmetry in the mouse. Development. 2002;129:4685-96 pubmed
    ..In the absence of embryonic Bmp4, the expression of left-side determinants such as Nodal and Lefty2 is absent in the left lateral plate mesoderm (LPM)...
  49. Migeotte I, Grego Bessa J, Anderson K. Rac1 mediates morphogenetic responses to intercellular signals in the gastrulating mouse embryo. Development. 2011;138:3011-20 pubmed publisher
    ..Rac1 also has essential roles in morphogenesis of the posterior notochordal plate (the node) and the midline. ..
  50. Meyers E, Martin G. Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science. 1999;285:403-6 pubmed
    ..In the mouse FGF8 is a left determinant and Sonic Hedgehog is required to prevent left determinants from being expressed on the right. ..
  51. Welsh I, O Brien T. Loss of late primitive streak mesoderm and interruption of left-right morphogenesis in the Ednrb(s-1Acrg) mutant mouse. Dev Biol. 2000;225:151-68 pubmed
    ..The expression of nodal and leftb, Tgf-beta-related genes involved in a left-determinant signaling pathway, is variably lost in the left lateral ..
  52. Sung Y, Baek I, Kim Y, Gho Y, Oh S, Lee Y, et al. PIERCE1 is critical for specification of left-right asymmetry in mice. Sci Rep. 2016;6:27932 pubmed publisher
    ..This is the first report implicating a role for PIERCE1 in the symmetry-breaking step of left-right asymmetry specification. ..
  53. Murray S, Gridley T. Snail family genes are required for left-right asymmetry determination, but not neural crest formation, in mice. Proc Natl Acad Sci U S A. 2006;103:10300-10304 pubmed publisher