An agent-based model of the Notch signaling pathway elucidates three levels of complexity in the determination of developmental patterning

Authored by Elaine R Reynolds, Ryan Himmelwright, Christopher Sanginiti, Jeffrey O Pfaffmann

Date Published: 2019

DOI: 10.1186/s12918-018-0672-9

Sponsors: No sponsors listed

Platforms: NetLogo

Model Documentation: Other Narrative

Model Code URLs: https://static-content.springer.com/esm/art%3A10.1186%2Fs12918-018-0672-9/MediaObjects/12918_2018_672_MOESM1_ESM.txt

Abstract

BackgroundThe Notch signaling pathway is involved in cell fate decision and developmental patterning in diverse organisms. A receptor molecule, Notch (N), and a ligand molecule (in this case Delta or Dl) are the central molecules in this pathway. In early Drosophila embryos, these molecules determine neural vs. skin fates in a reproducible rosette pattern.ResultsWe have created an agent-based model (ABM) that simulates the molecular components for this signaling pathway as agents acting within a spatial representation of a cell. The model captures the changing levels of these components, their transition from one state to another, and their movement from the nucleus to the cell membrane and back to the nucleus again. The model introduces stochastic variation into the system using a random generator within the Netlogo programming environment. The model uses these representations to understand the biological systems at three levels: individual cell fate, the interactions between cells, and the formation of pattern across the system. Using a set of assessment tools, we show that the current model accurately reproduces the rosette pattern of neurons and skin cells in the system over a wide set of parameters. Oscillations in the level of the N agent eventually stabilize cell fate into this pattern. We found that the dynamic timing and the availability of the N and Dl agents in neighboring cells are central to the formation of a correct and stable pattern. A feedback loop to the production of both components is necessary for a correct and stable pattern.ConclusionsThe signaling pathways within and between cells in our model interact in real time to create a spatially correct field of neurons and skin cells. This model predicts that cells with high N and low Dl drive the formation of the pattern. This model also be used to elucidate general rules of biological self-patterning and decision-making.

Tags

Simulation Agent-based modeling lateral inhibition Feedback Expression In-vivo Delta Canalization Notch signaling pathway Self-patterning