title: The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt.
abstract: The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch's interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain its neighbours in mitotically active states.
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, U.K.
authors.forename: Sophie K
authors.identifier: 0000-0002-1623-9265
authors.initials: SK
authors.lastname: Kay
authors.affiliation: Mathematical Institute, University of Oxford, Oxford, U.K.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Harrington
authors.affiliation: School of Mathematical Sciences, University of Nottingham, Nottingham, U.K.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shepherd
authors.affiliation: Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester, U.K.
authors.forename: Keith
authors.identifier: 0000-0002-9384-125X
authors.initials: K
authors.lastname: Brennan
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, U.K.
authors.forename: Trevor
authors.initials: T
authors.lastname: Dale
authors.affiliation: School of Mathematics and Statistics, University of Melbourne, Melbourne, Australia.
authors.forename: James M
authors.identifier: 0000-0002-5622-0104
authors.initials: JM
authors.lastname: Osborne
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, U.K.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gavaghan
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, U.K.|Mathematical Institute, University of Oxford, Oxford, U.K.
authors.forename: Helen M
authors.identifier: 0000-0003-1771-5910
authors.initials: HM
authors.lastname: Byrne
mesh_terms: D001683:Biological Clocks / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008954:Models, Biological; D020239:Receptor Cross-Talk / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072056:Transcription Factor HES-1 / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human