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]


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

David S. Parker1*{dagger}, Michael A. White2*, Andrea I. Ramos1, Barak A. Cohen2, and Scott Barolo1{ddagger}

1 Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109–2200, USA.
2 Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.

* These authors contributed equally to this work.

{dagger} Present address: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.

Abstract: Gradients of diffusible signaling proteins control precise spatial patterns of gene expression in the developing embryo. Here, we use quantitative expression measurements and thermodynamic modeling to uncover the cis-regulatory logic underlying spatially restricted gene expression in a Hedgehog (Hh) gradient in Drosophila. When Hh signaling is low, the Hh effector Gli, known as Cubitus interruptus (Ci) in Drosophila, acts as a transcriptional repressor; when Hh signaling is high, Gli acts as a transcriptional activator. Counterintuitively and in contrast to previous models of Gli-regulated gene expression, we found that low-affinity binding sites for Ci were required for proper spatial expression of the Hh target gene decapentaplegic (dpp) in regions of low Hh signal. Three low-affinity Ci sites enabled expression of dpp in response to low signal; increasing the affinity of these sites restricted dpp expression to regions of maximal signaling. A model incorporating cooperative repression by Ci correctly predicted the in vivo expression of a reporter gene controlled by a single Ci site. Our work clarifies how transcriptional activators and repressors, competing for common binding sites, can transmit positional information to the genome. It also provides an explanation for the widespread presence of conserved, nonconsensus Gli binding sites in Hh target genes.

{ddagger} To whom correspondence should be addressed. E-mail: sbarolo{at}

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