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Dev Cell. 2014 Nov 24;31(4):448-60. doi: 10.1016/j.devcel.2014.10.017. Epub 2014 Nov 24.

A predictive model of bifunctional transcription factor signaling during embryonic tissue patterning.

Author information

1
Departments of Physics and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Hubrecht Institute, KNAW, and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands.
2
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.
3
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Departments of Physics and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Hubrecht Institute, KNAW, and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands. Electronic address: a.vanoudenaarden@hubrecht.eu.

Abstract

Hedgehog signaling controls pattern formation in many vertebrate tissues. The downstream effectors of the pathway are the bifunctional Gli transcription factors, which, depending on hedgehog concentration, act as either transcriptional activators or repressors. Quantitatively understanding the interplay between Gli activator and repressor forms for patterning complex tissues is an open challenge. Here, we describe a reductionist mathematical model for how Gli activators and repressors are integrated in space and time to regulate transcriptional outputs of hedgehog signaling, using the pathway readouts Gli1 and Ptch1 as a model system. Spatially resolved measurements of absolute transcript numbers for these genes allow us to infer spatiotemporal variations of Gli activator and repressor levels. We validate our model by successfully predicting expression changes of Gli1 and Ptch1 in mutants at different developmental stages and in different tissues. Our results provide a starting point for understanding gene regulation by bifunctional transcription factors during mammalian development.

PMID:
25458012
DOI:
10.1016/j.devcel.2014.10.017
[Indexed for MEDLINE]
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