Presomitic mesoderm-specific expression of the transcriptional repressor Hes7 is controlled by E-box, T-box, and Notch signaling pathways

Abstract

Somites are a pair of epithelial spheres beside a neural tube and are formed with an accurate periodicity during embryogenesis in vertebrates. It has been known that Hes7 is one of the core clock genes for somitogenesis, and its expression domain is restricted in the presomitic mesoderm (PSM). However, the molecular mechanism of how Hes7 transcription is regulated is not clear. Here, using transgenic mice and luciferase-based reporter assays and in vitro binding assays, we unravel the mechanism by which Hes7 is expressed exclusively in the PSM. We identified a Hes7 essential region residing -1.5 to -1.1 kb from the transcription start site of mouse Hes7, and this region was indispensable for PSM-specific Hes7 expression. We also present detailed analyses of cis-regulatory elements within the Hes7 essential region that directs Hes7 expression in the PSM. Hes7 expression in the PSM was up-regulated through the E-box, T-box, and RBPj-binding element in the Hes7 essential region, presumably through synergistic signaling involving mesogenin1, T-box6 (Tbx6), and Notch. Furthermore, we demonstrate that Tbx18, Ripply2, and Hes7 repress the activation of the Hes7 essential region by the aforementioned transcription factors. Our findings reveal that a unified transcriptional regulatory network involving a Hes7 essential region confers robust PSM-specific Hes7 gene expression.