Disease relevance of Lefty1

• We have investigated the expression of left/right (L/R) asymmetry markers, nodal and lefty, in the situs inversus mouse mutant Fused toes (Ft) [1].
• We report the structure, chromosomal localization and expression features of Stra3, a novel mouse gene whose expression is upregulated by retinoic acid in P19 embryonal carcinoma cells [2].
• Here, we report on the effect of lefty, a novel member of the TGF-beta family, on the homeostasis of extracellular matrix in a fibrosarcoma model [3].
• Lefty was increased in the endometria of a number of patients with 'unexplained infertility' during the receptive phase, suggesting dysregulation of lefty as a potential factor contributing to infertility [4].

High impact information on Lefty1

• 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."[5]
• Asymmetric expression patterns of the genes nodal and lefty are reversed in the inv mutant, indicating that inv may act early in left/right determination [6].
• Lefty protein contains the cysteine-knot motif characteristic of this superfamily and is secreted as a processed form of relative molecular mass 25K-32K [7].
• In vertebrates, specification of anteroposterior (A/P) and left-right (L/R) axes depends on TGFbeta-related signals, including Nodal, Lefty, and BMPs [8].
• In contrast, the asymmetric expression of lefty-1 was shown to be determined by a combination of bilateral enhancers and a right side-specific silencer (RSS) [9].

Biological context of Lefty1

• These two genes are tightly linked on mouse chromosome 1. lefty-1 and lefty-2 are both expressed in a L-R asymmetric fashion in mouse embryos [10].
• RESULTS: We have identified two highly conserved genes, lefty-1 and lefty-2, in the mouse genome [10].
• The mutation of the consensus sequences for PC cleavage in the lefty protein allowed the lefty cleavage sites to be identified [11].
• Recently, we showed that, during undisturbed estrous cycle, lefty is present in mouse uterine horn primarily in a precursor form [12].
• Taken together, the findings show that decidualized differentiation of stroma, which is a prerequisite for embryo implantation, leads to processing of lefty by PC5/6A [12].

Anatomical context of Lefty1

• Our findings provide support for a model whereby Cerberus-like and Lefty1 in the anterior visceral endoderm restrict primitive streak formation to the posterior end of mouse embryos by antagonizing Nodal signaling [13].
• Lefty1 expression begins randomly in the inner cell mass (ICM) of the blastocyst but is regionalized to one side of the tilted ICM shortly after implantation [14].
• Asymmetric expression of Lefty1 can be established by in vitro culture, indicating that it does not require interaction with the uterus [14].
• In animal cap explants, Lefty-1 and Lefty-2 induce neural cells in the absence of mesoderm induction [10].
• Decidual differentiation of stromal cells promotes Proprotein Convertase 5/6 expression and lefty processing [12].

Associations of Lefty1 with chemical compounds

• We also demonstrate that retinoic acid (RA) controls Lefty-1 expression in a pathway downstream or parallel to Shh [15].
• There are four exons in the Stra3/lefty gene and its 5' flanking region contains, among other putative regulatory elements, an unusual retinoid response element consisting of two half sites arranged as a palindrome, with an 8 base pairs spacer [2].
• We present evidence, using transient transfection and antibody neutralization approaches, that Lefty-1 modulates the induction of alkaline phosphatase (ALP) after treatment of MC3T3-E1 cells with ascorbate and beta-GP [16].
• This state of overexpression could be induced by a retroviral vector transducing lefty or by liposome-mediated introduction of a lefty expression vector [4].

Regulatory relationships of Lefty1

• Ectopic Nodal expression in right LPM also induced Lefty1 expression in the floor plate [17].
• Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1 [15].

Other interactions of Lefty1

• Left-right asymmetric signaling molecules in mammals include three transforming growth factor beta (TGFbeta)-related factors, Nodal, Lefty1 and Lefty2 [18].
• TGFbeta-related genes such as lefty and nodal are L-R asymmetrically expressed in developing mouse embryos, and may be involved in L-R determination [10].
• This defect is not rescued in chimeras containing wild-type embryonic, and Cerberus-like(-/-);Lefty1(-/-) extraembryonic, cells but is rescued in Cerberus-like(-/-); Lefty1(-/-) embryos after removal of one copy of the Nodal gene [13].
• Nodal signaling thus initiates asymmetric Nodal expression in LPM and induces Lefty1 at the midline [17].
• However loss of the ASE disrupts Lefty2 (Leftb) expression and causes delayed Pitx2 expression leading to late onset, relatively minor LR patterning defects [19].

Analytical, diagnostic and therapeutic context of Lefty1

• RT-PCR and real-time PCR were used to identify mRNA expression and western blots to analyse Lefty protein [20].

References