Lefty was first identified in a screen for undifferentiated cell-specific cDNAs from the P19 mouse embryonal carcinoma cells. Its mRNA expression on the left side of the developing embryo earned it the name “lefty”. Two genes exist in mouse (Lefty-1 and Lefty-2) and two in humans (Lefty-A (ebaf) and Lefty-B). By amino acid sequence, mouse Lefty-1 and -2 are more similar to each other (90%) than to either Lefty-A or -B in humans (81 - 82% identical). Lefty contains the six cysteine residues that are conserved among TGF-beta related proteins and that are necessary to form the cysteine-knot structure. However, lefty is distinct from other family members in that it has two RXXR cleavage sites, a longer carboxy terminal sequence, and it lacks the cysteine residue required for intermolecular disulfide linkage. Thus, mature forms of lefty are larger than mature forms of other TGF-beta -related proteins. Mouse Lefty-1 is differentially processed depending on the cells in which it is synthesized, and both processing sites can be utilized.
Lefty homologues have been identified in other vertebrate organisms including chick, frog, and zebrafish. Although the amino acid sequence identity is not well conserved among vertebrate species, the expression pattern of lefty on the left side is well conserved. Lefty-1 is expressed strongly on the left side of the prospective floor plate and weakly in the left half of the lateral plate mesoderm in E8 mice embryos. In all species examined, lefty proteins function in patterning left-right asymmetry of the developing organ systems such as the heart and lung. Lefty acts as an antagonist to Nodal signaling, potentially by competing for binding to a common receptor.
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