Research ArticleDevelopmental Biology

The cis-Regulatory Logic of Hedgehog Gradient Responses: Key Roles for Gli Binding Affinity, Competition, and Cooperativity

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Science Signaling  07 Jun 2011:
Vol. 4, Issue 176, pp. ra38
DOI: 10.1126/scisignal.2002077

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Interpreting a Gradient Through Cooperative Repression

Hedgehog (Hh) signaling is required for tissue patterning during development. In the absence of Hh, the transcription factor Cubitus interruptus (Ci) in Drosophila is cleaved to generate a repressor form, whereas it is converted to an activator form in the presence of Hh. Gradients of ligands of the Hh family thus produce opposing gradients of repressor and activator forms of Ci. Both forms of Ci bind to the same enhancer elements in the promoter regions of target genes. One model of Hh morphogen activity implies that high-affinity binding sites for Ci should confer a broader expression domain for a gene. However, Parker et al. (see also the Perspective by Whitington et al.) noted that the enhancer of a broadly expressed Hh target gene decapentaplegic (dpp) contains low-affinity sites for Ci, whereas high-affinity sites are present in the enhancer of a Hh target gene with a more restricted expression pattern, patched (ptc). Reporter gene assays indicated that low-affinity binding sites for Ci were required for dpp to be expressed in areas of low Hh signal in Drosophila imaginal discs. Replacing the low-affinity Ci binding sites in the dpp enhancer with the higher-affinity Ci binding sites from ptc limited expression of dpp to areas of high Hh signal and caused severe developmental defects. Computational modeling, supported by in vivo experiments in flies, suggested that these results were best explained by cooperative binding of the repressor forms of Ci to enhancers and predicted that a single high-affinity site would mediate gene transcription in response to intermediate Hh signal, whereas three high-affinity sites would cause transcriptional repression. Thus, transcriptional responses to gradients of Hh are shaped by competition between repressor and activator forms for binding sites, the affinity of transcription factor binding sites, and cooperative binding of repressor forms.

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