Modeling Wnt/β-Catenin Target Gene Expression in APC and Wnt Gradients Under Wild Type and Mutant Conditions

Frontiers in Physiology
Uwe BenaryJana Wolf

Abstract

The Wnt/β-catenin pathway is involved in the regulation of a multitude of physiological processes by controlling the differential expression of target genes. In certain tissues such as the adult liver, the Wnt/β-catenin pathway can attain different levels of activity due to gradients of Wnt ligands and/or intracellular pathway components like APC. How graded pathway activity is converted into regionally distinct patterns of Wnt/β-catenin target gene expression is largely unknown. Here, we apply a mathematical modeling approach to investigate the impact of different regulatory mechanisms on target gene expression within Wnt or APC concentration gradients. We develop a minimal model of Wnt/β-catenin signal transduction and combine it with various mechanisms of target gene regulation. In particular, the effects of activation, inhibition, and an incoherent feedforward loop (iFFL) are compared. To specify activation kinetics, we analyze experimental data that quantify the response of β-catenin/TCF reporter constructs to different Wnt concentrations, and demonstrate that the induction of these constructs occurs in a cooperative manner with Hill coefficients between 2 and 5. In summary, our study shows that the combination of specific...Continue Reading

Citations

Nov 22, 2015·Nucleic Acids Research·Liang LiuXiaobo Zhou
Jan 22, 2013·Biochimica Et Biophysica Acta·Maged Zeineldin, Kristi L Neufeld
Jul 20, 2016·PLoS Computational Biology·Diego A VargasMuhammad H Zaman
Dec 19, 2017·Frontiers in Physiology·Bruno ChristNavina Waschinsky
Apr 17, 2019·PLoS Computational Biology·Alexis PietakMichael Levin
Mar 28, 2019·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Michael E SeifertRoslyn B Mannon
Mar 7, 2015·Physical Biology·Vladimir P Zhdanov, Fredrik Höök
Oct 11, 2017·Theoretical Biology & Medical Modelling·Kelsey GasiorSudin Bhattacharya
Feb 11, 2020·Experimental & Molecular Medicine·Youn-Sang Jung, Jae-Il Park

Related Concepts

Gene Activation
Gene Expression
Genes
Genes, Regulator
Ligands
Liver
Physiological Processes
Signal Transduction
Hepatocyte Nuclear Factor 1-beta
APC gene

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