Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 7 June 2011
Vol. 4, Issue 176, p. ra38
[DOI: 10.1126/scisignal.2002077]


Editor's Summary

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.

Citation: D. S. Parker, M. A. White, A. I. Ramos, B. A. Cohen, S. Barolo, The cis-Regulatory Logic of Hedgehog Gradient Responses: Key Roles for Gli Binding Affinity, Competition, and Cooperativity. Sci. Signal. 4, ra38 (2011).

Read the Full Text

A model of spatially restricted transcription in opposing gradients of activators and repressors.
M. A. White, D. S. Parker, S. Barolo, and B. A. Cohen (2014)
Mol Syst Biol 8, 614
   Abstract »    Full Text »    PDF »
Massively parallel synthetic promoter assays reveal the in vivo effects of binding site variants.
I. Mogno, J. C. Kwasnieski, and B. A. Cohen (2013)
Genome Res. 23, 1908-1915
   Abstract »    Full Text »    PDF »
Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning.
K. A. Peterson, Y. Nishi, W. Ma, A. Vedenko, L. Shokri, X. Zhang, M. McFarlane, J.-M. Baizabal, J. P. Junker, A. van Oudenaarden, et al. (2012)
Genes & Dev. 26, 2802-2816
   Abstract »    Full Text »    PDF »
Differential regulation of mesodermal gene expression by Drosophila cell type-specific Forkhead transcription factors.
X. Zhu, S. M. Ahmad, A. Aboukhalil, B. W. Busser, Y. Kim, T. R. Tansey, A. Haimovich, N. Jeffries, M. L. Bulyk, and A. M. Michelson (2012)
Development 139, 1457-1466
   Abstract »    Full Text »    PDF »
Beyond the Balance of Activator and Repressor.
T. Whitington, A. Jolma, and J. Taipale (2011)
Science Signaling 4, pe29
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882