Ultraconserved non-coding sequence element controls a subset of spatiotemporal GLI3 expression

The zinc-finger transcription factor GLI3 acts during vertebrate development in a combinatorial, context-dependent fashion as a primary transducer of sonic hedgehog (SHH) signaling. In humans, mutations affecting this key regulator of development are associated with GLI3-morphopathies, a group of congenital malformations in which forebrain and limb development are preferentially affected. We show that a non-coding element from intron two of GLI3, ultraconserved in mammals and highly conserved in the pufferfish Fugu, is a transcriptional enhancer. In transient transfection assays, it activates reporter gene transcription in human cell cultures expressing endogenous GLI3 but not in GLI3 negative cells. The identified enhancer element is predicted to contain conserved binding sites for transcription factors crucial for developmental steps in which GLI3 is involved. The regulatory potential of this element is conserved and was used to direct tissue-specific expression of a green fluorescent protein reporter gene in zebrafish embryos and of a beta-galactosidase reporter in transgenic mouse embryos. Time, location, and quantity of reporter gene expression are congruent with part of the pattern previously reported for endogenous GLI3 transcription.

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