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Background  The zinc-finger transcription factor GLI3 is an important mediator of Sonic hedgehog signaling and crucial for patterning of many aspects of the vertebrate body plan. In vertebrates, the mechanism of SHH signal transduction and its action on target genes by means of activating or repressing forms of GLI3 have been studied most extensively during limb development and the specification of the central nervous system. From these studies it has emerged, that  Gli3  expression must be subject to a tight spatiotemporal regulation. However, the genetic mechanisms and the cis-acting elements controlling the expression of  Gli3  remained largely unknown.    Results  Here, we demonstrate in chicken and mouse transgenic embryos that human  GLI3 -intronic conserved non-coding sequence elements (CNEs) autonomously control individual aspects of  Gli3  expression. Their combined action shows many aspects of a  Gli3 -specific pattern of transcriptional activity. In the mouse limb bud, different CNEs enhance  Gli3 -specific expression in evolutionary ancient stylopod and zeugopod versus modern skeletal structures of the autopod. Limb bud specificity is also found in chicken but had not been detected in zebrafish embryos. Three of these elements govern central nervous system specific gene expression during mouse embryogenesis, each targeting a subset of endogenous  Gli3  transcription sites. Even though fish, birds, and mammals share an ancient repertoire of gene regulatory elements within  Gli3 , the functions of individual enhancers from this catalog have diverged significantly. During evolution, ancient broad-range regulatory elements within  Gli3  attained higher specificity, critical for patterning of more specialized structures, by abolishing the potential for redundant expression control.    Conclusion  These results not only demonstrate the high level of complexity in the genetic mechanisms controlling  Gli3  expression, but also reveal the evolutionary significance of  cis -acting regulatory networks of early developmental regulators in vertebrates.

Human intronic enhancers control distinct sub-domains of Gli3 expression during mouse CNS and limb development