Limits on the accuracy of contact inhibition of locomotion

TL;DR

This paper presents a theoretical model analyzing the limits of contact inhibition of locomotion (CIL) in cells, showing how factors like ligand interference and contact width affect the cell's ability to accurately detect cell contact.

Contribution

The study introduces a quantitative model for CIL recognition limits, incorporating ligand interference and contact geometry, providing insights into the reliability of cellular contact sensing.

Findings

Cells can reliably detect micron-scale contacts despite ligand interference.

Recognition accuracy decreases with smaller contact widths and higher ligand interference.

Error rates are influenced by contact size and ligand concentration, but spatial boundary information helps maintain accuracy.

Abstract

Cells that collide with each other repolarize away from contact, in a process called contact inhibition of locomotion (CIL), which is necessary for correct development of the embryo. CIL can occur even when cells make a micron-scale contact with a neighbor - much smaller than their size. How precisely can a cell sense cell-cell contact and repolarize in the correct direction? What factors control whether a cell recognizes it has contacted a neighbor? We propose a theoretical model for the limits of CIL where cells recognize the presence of another cell by binding the protein ephrin with the Eph receptor. This recognition is made difficult by the presence of interfering ligands that bind nonspecifically. Both theoretical predictions and simulation results show that it becomes more difficult to sense cell-cell contact when it is difficult to distinguish ephrin from the interfering ligands, or when there are more interfering ligands, or when the contact width decreases. However, the error of estimating contact position remains almost constant when the contact width changes. This happens because the cell gains spatial information largely from the boundaries of cell-cell contact. We study using statistical decision theory the likelihood of a false positive CIL event in the absence of cell-cell contact, and the likelihood of a false negative where CIL does not occur when another cell is present. Our results suggest that the cell is more likely to make incorrect decisions when the contact width is very small or so large that it nears the cell's perimeter. However, in general, we find that cells have the ability to make reasonably reliable CIL decisions even for very narrow (micron-scale) contacts, even if the concentration of interfering ligands is ten times that of the correct ligands.