title: A predictive model of bifunctional transcription factor signaling during embryonic tissue patterning.
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.
authors.affiliation: 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.
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Junker
authors.affiliation: 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.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Peterson
authors.affiliation: 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.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nishi
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Junhao
authors.initials: J
authors.lastname: Mao
authors.affiliation: 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.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1