Distinct transcriptional regulatory mechanisms underlie left–right asymmetric expression of lefty-1 and lefty-2

Distinct transcriptional regulatory mechanisms underlie left–right asymmetric expression of lefty-1 and lefty-2

Division of Molecular Biology, Institute for Molecular and Cellular Biology, Osaka University, Suita, Osaka 565, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST)

Abstract

Both lefty-1 and lefty-2 genes are expressed on the left side of developing mouse embryos and are implicated in left–right (L–R) axis formation. With the use of transgenic analysis, the transcriptional regulatory regions of these genes responsible for their L–R asymmetric expression have now been investigated. The 9.5-kb upstream region of lefty-1 and the 5.5-kb upstream region oflefty-2 reproduced the expression pattern of the corresponding gene. Examination of deletion constructs revealed the presence of a left side-specific enhancer (ASE) that is essential and sufficient forlefty-2 asymmetric expression. 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). The 9.5-kb region of lefty-1 and the 5.5-kb region oflefty-2 responded to iv and inv, upstream genes of lefty-1 and lefty-2. The regulation oflefty-2 by iv and inv was mediated by ASE. These results suggest that, in spite of the similarities betweenlefty-1 and lefty-2, different regulatory mechanisms underlie their asymmetric expression.