The Role of the Hes1 Crosstalk Hub in Notch-Wnt Interactions of the Intestinal Crypt

TL;DR

This study introduces a mathematical model of Notch and Wnt pathways focusing on Hes1 as a crosstalk hub, revealing how Wnt influences cell fate decisions in intestinal tissue through pathway stability and dynamics.

Contribution

The paper presents a novel mathematical model integrating Notch and Wnt pathways with Hes1 as a central crosstalk hub, using CRNT to analyze pathway stability and dynamics.

Findings

Wnt stabilizes Notch pathway and reduces oscillations.

Wnt-mediated Hes1 transcription promotes bistability.

Model predicts effects of biochemical knockouts on cell fate.

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 beta-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamical 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 beta-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.