An ancient transcriptional regulatory linkage.

Changes in gene regulatory networks are a major engine for creating developmental novelty during evolution. Conversely, regulatory linkages that survive for very long evolutionary periods might be characteristic of ancient and abstract functions of fundamental utility to all metazoans. The proneural genes, which encode a distinctive family of basic helix-loop-helix (bHLH) transcriptional activators, act to promote neural cell fates in the ectoderm of diverse species. Here we report that these genes have been associated for at least 600-700 million years--since before the cnidarian/bilaterian divergence--with a high-affinity binding site for Hairy/Enhancer of split (Hes) repressor proteins. We suggest that the systematic identification of such ancient and conserved connections will be a powerful means of uncovering the primordial functions of transcription factors and signaling systems.