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Concentration Sensing by the Moving Nucleus in Cell Fate Determination: A Computational Analysis
Varun Aggarwal1, Richard B Dickinson1, Tanmay P Lele1
1Department of Chemical Engineering, University of Florida, Gainesville, Florida, United States of America.
Plos One
|February 13, 2016
Summary
Neural progenitor cell (NPC) fate is determined by nuclear Notch intracellular domain (NICD) levels. Mathematical modeling and simulations reveal how nuclear migration stochasticity is overcome to ensure accurate cell fate determination in zebrafish retina development.
Area of Science:
- Developmental Biology
- Cell Biology
- Computational Biology
Background:
- Neural progenitor cells (NPCs) undergo interkinetic nuclear migration (INM) during vertebrate neuroepithelium development.
- Nuclear position and movement are hypothesized to influence daughter cell fate via Notch signaling.
- The stochastic nature of nuclear migration complicates understanding how precise cell fate determination is achieved.
Purpose of the Study:
- To investigate the mechanism by which nuclear position determines neural progenitor cell fate despite stochastic nuclear migration.
- To quantify the relationship between nuclear NICD concentration and NPC differentiation probability.
- To assess the role of reaction, diffusion, and nuclear accumulation of NICD in cell fate determination.
Main Methods:
- Developed a mathematical model for NICD reaction, diffusion, and nuclear accumulation during INM.
- Performed stochastic simulations using experimentally measured NPC migration parameters from zebrafish retina.
- Estimated the cytoplasmic NICD gradient by comparing simulation results with experimental data on nuclear NICD concentrations and differentiation probabilities.
Main Results:
- Spatially polarized production of NICD, rapid cytoplasmic consumption, and nuclear import/export kinetics sufficiently explain observed NPC differentiation probabilities.
- The time-averaging effect of nuclear kinetics helps reconcile stochastic nuclear migration with precise cell fate determination.
- Computational studies provide quantitative support for a nuclear concentration-sensing mechanism in zebrafish retinal NPCs.
Conclusions:
- Nuclear concentration sensing of NICD is a feasible mechanism for determining neural progenitor cell fate.
- The interplay of NICD dynamics and nuclear migration kinetics ensures accurate cell fate decisions during development.
- This study offers a quantitative framework for understanding cell fate determination in the developing vertebrate nervous system.
