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Left-right determination factor B (Gene LEFTY1)The human LEFTY1 (map locus 1q42.1) gene product, left-right determination factor B/LEFTYB, is a 366 AA long (40.9 kDa) precursor protein that contains a 26 AA signal sequence (1 to 26), a variable propeptide and a 290 AA (long form) left-right determination factor 1 (77 to 366). Human LeftyA (Lefty2) and LeftyB (Lefty1) are separated by approximately 50 kb on chromosome 1q42 and both are derived from four exons spliced at identical positions, Kosaki K, et al. (1999). The LEFTYB propeptide may be processed at two RXXR sites (Arg77 or Arg135) leading to long (34 kDa) and short (28 kDa) forms of LeftyB, Yashiro K, (2000); Ulloa L, (2001). Lefty1 is cleaved by SPC1, SPC4, SPC6A and SPC6b at both sites; Sakuma R, et al. (2002), Constam DB, et al. (2000). The biological activity, stability and diffusion potential of Lefty1 may be dependent upon the forms present, Constam DB, et al. (2000). LeftyB (Lefty1) is involved in several embryonic developmental processes. Expression in early embryonic cell populations antagonizes TGFbeta factors like Nodal to drive differentiation towards neuroectoderm; at later stages Lefty1 and Lefty2 are essential factors for the development of leftness in left-right asymmetry (L-R asymmetry) development of the embryo. Recently a role for the Lefty proteins in growth of differentiated cells has emerged. Lefty proteins are transiently expressed during human embryonic stem cell differentiation. The Lefty proteins are exclusively expressed by human embryoid body cell populations (cadherin 2 and 11 positive) that do not overlap the OCT4 expressing cell populations. These Lefty containing cells, which are mesoderm progenitor-like (Nodal positive), represent an early differentiation step towards embryonic germ layers, Dvash T, et al. (2007). Overexpression of Lefty in Nodal positive cells induces differentiation towards a neuroectodermal default pathway, Smith JR, et al. (2008). Lefty expression in the embryonic node is controlled by the Activin/Nodal/Smad2/3 branch of the TGFbeta pathway, Besser D. (2004) and the Wnt pathway, Hamada H, et al. (2002). Lefty1 is required for the establishment of left-right (L-R) asymmetry in the early embryo. Lefty1, which is expressed in the prospective floor plate (PFP), left side of the ventral neural tube, restricts Nodal, Lefty2 and Pitx2 expression to the left side lateral plate mesoderm (LPM), Meno C, et al. (1997, 1998). In late somite-stage embryos, lefty1 is expressed asymmetrically in the left diencephalon, Bisgrove BW, et al. (1999). The left side expression of lefty-1 (antivin in Danio rerio, zebrafish) is also reported in chick embryo, Ishimaru Y, et al. (2000). Bilateral symmetry is maintained by antagonistic interactions between the lefty proteins and nodal subfamily members of the TGFbeta family, Bisgrove BW, et al. (1999). The nodal-related ligands of zebrafish, Squint and Cyclopes, are antagonized by the Lefty1 and Lefty2. Loss of Lefty1 causes aberrations during somitogenesis, including left-right patterning defects, Feldman B, et al. (2003). Lefty1 blocks signaling by TGFbeta family members Nodal and Nodal-related proteins, Vg1/GDF1 and GDF3 by at least two mechanisms. These TGFbeta factors require EGF-CFC co-receptors such as TDGF1/Cripto to be fully active. Lefty1 binds to EGF-CFC coreceptors and blocks their activity; Shakuma R, et al. (2002), Cheng SK, et al. (2004). The context-dependent interactions between Lefty and these factors enhance L-R asymmetry, Branford WW, et al. (2000). Lefty1 also binds to and blocks Nodal directly; Chen C and Shen MM (2004) and Chen C, et al. (2006). Lefty1 slightly precedes Lefty-2 expression beginning around the 2-somite pair stage, Heymer J, et al. (1997). Lefty1 is required to avoid LR-asymmetry dysregulation and to allow expression of Lefty2. Lefty1 is regulated by different and more complex signaling than lefty2. Lefty1 has a 9.5 kb upstream regulatory region and expression depends upon a combination of bilateral enhancers and right side-specific silencer (RSS). It is also responsive to inversus viscerum (iv) and inversion of embryo turning (inv). The RSS determines L-R asymmetry, Saijoh Y, et al. (1999). The expression of Lefty1 is regulated by retinoic acid (RA) and sonic hedgehog (Shh), Tsukui T, et al. (1999). The factor Pcl2 (in chick) silences Shh on the right side of Hensen’s node, Wang S, et al. (2004). Retinoic acid affects L-R patterning thru expression of lefty1, lefty2, nodal and pitx-2 in the lateral plate mesoderm, Wasiak S and Lohnes D. (1999). In zebrafish, cyclops is required for maintenance of Lefty1 and Lefty2 transcription, Feldman B, et al. (2003). Lefty1 may have a later role in cell growth and differentiation. Lefty1 and Nodal have been reported to play a role in the growth of pancreatic cells where Lefty1 activates MAPK and Akt phosphorylation, Zhang YQ et al. (2008). Lefty1 was reported to modulate the induction of alkaline phosphatase (ALP) in the bone development model cell line, MC3T3-E1, an osteoblast-like cell, Seth A, et al. (2000). Lefty2 downstream of Lefty 1 is important in embryo preimplantation and menstruation processes. Sigma offers antibodies and shRNAs useful for the study of LEFTY1 gene. References: Besser D. (2004) Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. J Biol Chem. 279: 45076-45084. |
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