Alternative titles; symbols
HGNC Approved Gene Symbol:LEFTY1
Cytogenetic location:1q42.12 Genomic coordinates(GRCh38) :1:225,886,282-225,889,146 (from NCBI)
Vertebrates exhibit numerous left-right (L-R) asymmetries, such as the position of the heart and spleen on the left side. L-R polarity is determined early during development, around the presomite stage in mammals. Several genes have been shown to be expressed asymmetrically relative to the L-R axis. Meno et al. (1996,1997) identified 2 transforming growth factor-beta-related genes, Lefty1 and Lefty2 (601887), that are expressed on the left side of developing mouse embryos. A human sequence corresponding to the mouse Lefty2 gene has been deposited in the GenBank database (AF081507).
Kosaki et al. (1999) characterized 2 homologs of the murine Lefty1 and Lefty2 genes, which they designated LEFTY B and LEFTY A, respectively. Both genes encode proteins with 366 amino acids. The deduced amino acid sequences of LEFTY B and LEFTY A are more similar to each other than to mouse Lefty1 or Lefty2.
Kosaki et al. (1999) determined that the LEFTY1 and LEFTY2 genes each comprise 4 exons spliced at identical positions. The genes are separated by approximately 50 kb on chromosome 1q42.
Kosaki et al. (1999) mapped the LEFTY1 and LEFTY2 genes to chromosome 1q42 by FISH.
For a discussion of LEFTY2 and the mutations identified in that gene in cases of left-right axis malformations, see601877.
Lefty1, Lefty2, and Nodal (601265) are expressed on the left side of developing mouse embryos and are implicated in L-R determination.Meno et al. (1998) examined the role of Lefty1 by analyzing mutant mice lacking this gene. The Lefty1-deficient mice showed a variety of L-R positional defects in visceral organs. The most common feature of Lefty1 -/- mice was thoracic left isomerism (rather than right isomerism). The lack of Lefty1 resulted in bilateral expression of Nodal, Lefty2, and Pitx2 (601542), a homeobox gene normally expressed on the left side. These observations suggested that the role of Lefty1 is to restrict the expression of Lefty2 and Nodal to the left side, and that Lefty2 or Nodal encode a signal for 'leftness.'
In mouse embryos,Takaoka et al. (2006) found that Lefty1 was asymmetrically expressed in the primitive endoderm of the implanting blastocyst. Lefty1 expression began randomly in the inner cell mass of the blastocyst but became regionalized to one side of the tilted inner cell mass shortly after implantation. Asymmetric Lefty1 expression was established by in vitro culture, indicating that it does not require interaction with the uterus. Asymmetric Lefty1 expression was induced by Nodal signaling, although Nodal and genes for its effectors were expressed symmetrically.Takaoka et al. (2006) concluded that asymmetric patterning of the mouse embryo along the anteroposterior axis begins in the periimplantation stage.
Reaction-diffusion models postulated that differences in signaling range are caused by differential diffusivity of inhibitor and activator. Other models suggested that differential clearance underlies different signaling ranges. To test these models,Muller et al. (2012) measured the biophysical properties of the Nodal/Lefty activator/inhibitor system during zebrafish embryogenesis. Analysis of Nodal and Lefty gradients revealed that Nodals have a shorter range than Lefty proteins. Pulse-labeling analysis indicated that Nodals and Leftys have similar clearance kinetics, whereas fluorescence recovery assays revealed that Leftys have a higher effective diffusion coefficient than Nodals.Muller et al. (2012) concluded that their results indicated that differential diffusivity is the major determinant of the differences in Nodal/Lefty range and provided biophysical support for reaction-diffusion models of activator/inhibitor-mediated patterning.
Montague et al. (2018) found that zebrafish homozygous for single and double frameshift null mutations in spaw (the zebrafish ortholog of Nodal), dand5 (609068), and lefty1 were viable and lacked gross phenotypes. However, all mutant combinations displayed randomized or symmetric heart looping and jogging, similar to their respective mouse mutants. Further analysis revealed that spaw induced its expression in lateral plate mesoderm and was required for proper heart asymmetry in zebrafish, whereas dand5 and lefty1 were inhibitors of spaw and regulated the timing and speed of spaw propagation.
Kosaki, K., Bassi, M. T., Kosaki, R., Lewin, M., Belmont, J., Schauer, G., Casey, B.Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am. J. Hum. Genet. 64: 712-721, 1999. [PubMed:10053005,related citations] [Full Text]
Meno, C., Ito, Y., Saijoh, Y., Matsuda, Y., Tashiro, K., Kuhara, S., Hamada, H.Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neutralizing activity in Xenopus embryos. Genes Cells 2: 513-524, 1997. [PubMed:9348041,related citations] [Full Text]
Meno, C., Saijoh, Y., Fujii, H., Ikeda, M., Yokoyama, T., Yokoyama, M., Toyoda, Y., Hamada, H.Left-right asymmetric expression of the TGF-beta-family member lefty in mouse embryos. Nature 381: 151-155, 1996. [PubMed:8610011,related citations] [Full Text]
Meno, C., Shimono, A., Saijoh, Y., Yashiro, K., Mochida, K., Ohishi, S., Noji, S., Kondoh, H., Hamada, H.Lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94: 287-297, 1998. [PubMed:9708731,related citations] [Full Text]
Montague, T. G., Gagnon, J. A., Schier, A. F.Conserved regulation of Nodal-mediated left-right patterning in zebrafish and mouse. Development 145: dev171090, 2018. [PubMed:30446628,images,related citations] [Full Text]
Muller, P., Rogers, K. W., Jordan, B. M., Lee, J. S., Robson, D., Ramanathan, S., Schier, A. F.Differential diffusivity of Nodal and Lefty underlies a reaction-diffusion patterning system. Science 336: 721-724, 2012. [PubMed:22499809,images,related citations] [Full Text]
Takaoka, K., Yamamoto, M., Shiratori, H., Meno, C., Rossant, J., Saijoh, Y., Hamada, H.The mouse embryo autonomously acquires anterior-posterior polarity at implantation. Dev. Cell 10: 451-459, 2006. [PubMed:16580991,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: LEFTY1
Cytogenetic location: 1q42.12 Genomic coordinates(GRCh38) : 1:225,886,282-225,889,146(from NCBI)
Vertebrates exhibit numerous left-right (L-R) asymmetries, such as the position of the heart and spleen on the left side. L-R polarity is determined early during development, around the presomite stage in mammals. Several genes have been shown to be expressed asymmetrically relative to the L-R axis. Meno et al. (1996, 1997) identified 2 transforming growth factor-beta-related genes, Lefty1 and Lefty2 (601887), that are expressed on the left side of developing mouse embryos. A human sequence corresponding to the mouse Lefty2 gene has been deposited in the GenBank database (AF081507).
Kosaki et al. (1999) characterized 2 homologs of the murine Lefty1 and Lefty2 genes, which they designated LEFTY B and LEFTY A, respectively. Both genes encode proteins with 366 amino acids. The deduced amino acid sequences of LEFTY B and LEFTY A are more similar to each other than to mouse Lefty1 or Lefty2.
Kosaki et al. (1999) determined that the LEFTY1 and LEFTY2 genes each comprise 4 exons spliced at identical positions. The genes are separated by approximately 50 kb on chromosome 1q42.
Kosaki et al. (1999) mapped the LEFTY1 and LEFTY2 genes to chromosome 1q42 by FISH.
For a discussion of LEFTY2 and the mutations identified in that gene in cases of left-right axis malformations, see 601877.
Lefty1, Lefty2, and Nodal (601265) are expressed on the left side of developing mouse embryos and are implicated in L-R determination. Meno et al. (1998) examined the role of Lefty1 by analyzing mutant mice lacking this gene. The Lefty1-deficient mice showed a variety of L-R positional defects in visceral organs. The most common feature of Lefty1 -/- mice was thoracic left isomerism (rather than right isomerism). The lack of Lefty1 resulted in bilateral expression of Nodal, Lefty2, and Pitx2 (601542), a homeobox gene normally expressed on the left side. These observations suggested that the role of Lefty1 is to restrict the expression of Lefty2 and Nodal to the left side, and that Lefty2 or Nodal encode a signal for 'leftness.'
In mouse embryos, Takaoka et al. (2006) found that Lefty1 was asymmetrically expressed in the primitive endoderm of the implanting blastocyst. Lefty1 expression began randomly in the inner cell mass of the blastocyst but became regionalized to one side of the tilted inner cell mass shortly after implantation. Asymmetric Lefty1 expression was established by in vitro culture, indicating that it does not require interaction with the uterus. Asymmetric Lefty1 expression was induced by Nodal signaling, although Nodal and genes for its effectors were expressed symmetrically. Takaoka et al. (2006) concluded that asymmetric patterning of the mouse embryo along the anteroposterior axis begins in the periimplantation stage.
Reaction-diffusion models postulated that differences in signaling range are caused by differential diffusivity of inhibitor and activator. Other models suggested that differential clearance underlies different signaling ranges. To test these models, Muller et al. (2012) measured the biophysical properties of the Nodal/Lefty activator/inhibitor system during zebrafish embryogenesis. Analysis of Nodal and Lefty gradients revealed that Nodals have a shorter range than Lefty proteins. Pulse-labeling analysis indicated that Nodals and Leftys have similar clearance kinetics, whereas fluorescence recovery assays revealed that Leftys have a higher effective diffusion coefficient than Nodals. Muller et al. (2012) concluded that their results indicated that differential diffusivity is the major determinant of the differences in Nodal/Lefty range and provided biophysical support for reaction-diffusion models of activator/inhibitor-mediated patterning.
Montague et al. (2018) found that zebrafish homozygous for single and double frameshift null mutations in spaw (the zebrafish ortholog of Nodal), dand5 (609068), and lefty1 were viable and lacked gross phenotypes. However, all mutant combinations displayed randomized or symmetric heart looping and jogging, similar to their respective mouse mutants. Further analysis revealed that spaw induced its expression in lateral plate mesoderm and was required for proper heart asymmetry in zebrafish, whereas dand5 and lefty1 were inhibitors of spaw and regulated the timing and speed of spaw propagation.
Kosaki, K., Bassi, M. T., Kosaki, R., Lewin, M., Belmont, J., Schauer, G., Casey, B.Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am. J. Hum. Genet. 64: 712-721, 1999. [PubMed: 10053005] [Full Text: https://doi.org/10.1086/302289]
Meno, C., Ito, Y., Saijoh, Y., Matsuda, Y., Tashiro, K., Kuhara, S., Hamada, H.Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neutralizing activity in Xenopus embryos. Genes Cells 2: 513-524, 1997. [PubMed: 9348041] [Full Text: https://doi.org/10.1046/j.1365-2443.1997.1400338.x]
Meno, C., Saijoh, Y., Fujii, H., Ikeda, M., Yokoyama, T., Yokoyama, M., Toyoda, Y., Hamada, H.Left-right asymmetric expression of the TGF-beta-family member lefty in mouse embryos. Nature 381: 151-155, 1996. [PubMed: 8610011] [Full Text: https://doi.org/10.1038/381151a0]
Meno, C., Shimono, A., Saijoh, Y., Yashiro, K., Mochida, K., Ohishi, S., Noji, S., Kondoh, H., Hamada, H.Lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94: 287-297, 1998. [PubMed: 9708731] [Full Text: https://doi.org/10.1016/s0092-8674(00)81472-5]
Montague, T. G., Gagnon, J. A., Schier, A. F.Conserved regulation of Nodal-mediated left-right patterning in zebrafish and mouse. Development 145: dev171090, 2018. [PubMed: 30446628] [Full Text: https://doi.org/10.1242/dev.171090]
Muller, P., Rogers, K. W., Jordan, B. M., Lee, J. S., Robson, D., Ramanathan, S., Schier, A. F.Differential diffusivity of Nodal and Lefty underlies a reaction-diffusion patterning system. Science 336: 721-724, 2012. [PubMed: 22499809] [Full Text: https://doi.org/10.1126/science.1221920]
Takaoka, K., Yamamoto, M., Shiratori, H., Meno, C., Rossant, J., Saijoh, Y., Hamada, H.The mouse embryo autonomously acquires anterior-posterior polarity at implantation. Dev. Cell 10: 451-459, 2006. [PubMed: 16580991] [Full Text: https://doi.org/10.1016/j.devcel.2006.02.017]
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