Regulation of Slug transcription in embryonic ectoderm by beta-catenin-Lef/Tcf and BMP-Smad signaling.

Neural crest is formed at the boundary of epidermal and neural ectoderm. To understand the molecular mechanism of neural crest formation, we focused on the transcriptional regulation of the Slug gene. In the upstream sequence of the chicken Slug gene, we have identified potential binding sites for transcription factors, such as Lef/Tcf and Smad1. Transgenic mouse embryos carrying the chicken Slug promoter-reporter gene showed a crest-specific activation of the reporter, suggesting the isolated sequence included the cis-regulatory elements to receive Slug-inducing signals in the mouse neural crest. While these potential cis-regulatory elements could be recognized and activated by corresponding transcription factors, such as Lef1 and Smad1, Wnt-Lef-beta-catenin signal failed to induce endogenous Slug expression in quail neural plate tissue prepared from forebrain and midbrain levels. In contrast, Slug expression and subsequent epithelial-mesenchymal transition were effectively induced by BMP4. Consistently, while we could detect phosphorylation of Smad1 in the ectoderm including the neural plate and the neural fold region, the activation of a reporter gene for a detection of canonical Wnt signal activation was below the level of detection at the forebrain and midbrain levels. These observations indicated that in the anterior ectoderm BMP signal has a predominant role for Slug expression.