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

Abstract

Background: Vertebrates have numerous lateral asymmetries in the position of their organs, but the molecular basis for the determination of left–right (L‐R) asymmetries remains largely unknown. TGFβ‐related genes such as lefty and nodal are L‐R asymmetrically expressed in developing mouse embryos, and may be involved in L‐R determination. Results: We have identified two highly conserved genes, lefty‐1 and lefty‐2, in the mouse genome. 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. However, the major expression domains of the two genes are different: lefty‐1 expression is predominantly confied to the left side of ventral neural tube, whereas lefty‐2 is strongly expressed in the lateral plate mesoderm on the left side. In embryos homozygous for the iv and inv mutation, which cause situs inversus, the expression sites of both genes are affected, either reversed or bilaterally, indicating that lefty‐1 and lefty‐2 are downstream of iv and inv. Although Lefty‐1 and Lefty‐2 prepro‐proteins are not readily processed in cultured cells, BMP2‐Lefty chimeric proteins can be processed to a secreted form. We have examined the activities of Lefty‐1 and Lefty‐2 in Xenopus embryos. In animal cap explants, Lefty‐1 and Lefty‐2 induce neural cells in the absence of mesoderm induction. The direct neuralizing activities of Lefty‐1 and Lefty‐2 thus seem remarkably similar to those of BMP antagonists such as noggin and chordin, suggesting that the action of Lefty‐1 and Lefty‐2 may be to locally antagonize BMP (bone morphogenic protein)‐mediated signals in tissues positioned on the left side of the mouse embryos. Conclusion: There are two lefty genes in mice (lefty‐1 and lefty‐2), both of which are expressed in a L‐R asymmetric fashion and are downstream of iv and inv. Lefty‐1 and Lefty‐2 possess direct neuralizing activity in Xenopus embryos, resembling the activities of BMP antagonists.