Dorsal is a sequence-specific transcription factor that is distributed in a broad nuclear gradient across the dorsal-ventral (DV) axis of the early Drosophila embryo. It initiates gastrulation by regulating at least 30-50 target genes in a concentration-dependent fashion. Previous studies identified 18 enhancers that are directly regulated by different concentrations of Dorsal. Here, we employ computational methods to determine the basis for these distinct transcriptional outputs. Orthologous enhancers were identified in a variety of divergent Drosophila species, and their comparison revealed several conserved sequence features responsible for DV patterning. In particular, the quality of Dorsal and Twist recognition sequences correlates with the DV coordinates of gene expression relative to the Dorsal gradient. These findings are entirely consistent with a gradient threshold model for DV patterning, whereby the quality of individual Dorsal binding sites determines in vivo occupancy of target enhancers by the Dorsal gradient. Linked Dorsal and Twist binding sites constitute a conserved composite element in certain "type 2" Dorsal target enhancers, which direct gene expression in ventral regions of the neurogenic ectoderm in response to intermediate levels of the Dorsal gradient. Similar motif arrangements were identified in orthologous loci in the distant mosquito genome, Anopheles gambiae. We discuss how Dorsal and Twist work either additively or synergistically to activate different target enhancers.
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